A Phase I/II, Randomized, Placebo-controlled Comparative Study to Evaluate the Safety and Potential Efficacy of Intravenous Infusion of Umbilical Cord Tissue (UC) Derived Mesenchymal Stem Cells (MSCs) Versus Bone Marrow (BM) Derived MSCs to Evaluate Cytokine Suppression in Patients With Chronic Inflammation Due to Metabolic Syndrome.
Phase: PHASE1
Conditions: Endothelial Dysfunction, Metabolic Syndrome, Chronic Inflammation
Sponsor: Joshua M Hare

 
 
Interdisciplinary Stem Cell Institute 
University of Miami/ Miller School of Medicine 
Clinical Research Protocol 
Study Title:  
A Phase I/II, Randomized, Blinded, Placebo-controlled 
Comparative study to evaluate the Safety and Potential 
Efficacy of Intravenous Infusion of Umbilical Cord 
Tissue (UC) derived Mesenchymal Stem Cells (MSCs) 
Versus Bone Marrow (BM) derived MSCs to evaluate 
cytokine suppression in patients with chronic 
inflammation due to Metabolic Syndrome. The CERES 
Trial. 
 
Study Product: 
Allogeneic Umbilical Cord Tissue derived Mesenchymal 
Stem Cells (UCMSCs) and Bone Marrow derived Human 
Mesenchymal Stem Cells (BMMSCs) 
Indication:  
 
Metabolic Syndrome 
FDA IND No.:  
 
BB-IND #17324 
 
 
 
 
NCT No.: 
 
 
NCT03059355 
Protocol Version:  
 October 22, 2020 Version 3.8  
Sponsor /  
Principal Investigator: 
Joshua M. Hare, MD 
 
Telephone:  
 
(305) 243 – 5579  
Fax: 
 
 
 
(305) 243 – 5584  
Email: 
 
 
JHare@med.miami.edu 
 
 
_________________________________________ 
 
 
______________________ 
Joshua M. Hare, M.D   
 
 
 
 
Date 
(Sponsor-Investigator) 
 
 
 
 
 
CONFIDENTIALITY STATEMENT 
 
This document is confidential and proprietary to the Interdisciplinary Stem Cell Institute at the University of 
Miami/Miller School of Medicine and its affiliates.  Acceptance of this document constitutes agreement by the 
recipient that no unpublished information contained herein will be reproduced, published, or otherwise 
disseminated or disclosed without prior written approval of the Interdisciplinary Stem Cell Institute University 
of Miami or its affiliates, except that this document may be disclosed in any medium to appropriate clinical 
investigators, Institutional Review Boards, and others directly involved in the clinical investigation that is the 
subject of this information under the condition that they keep the information strictly confidential.

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Table of Contents 
 
Protocol Synopsis ............................................................................................................................................... 11 
1. 
INTRODUCTION .............................................................................................................................. 15 
1.1 
Background ....................................................................................................................................... 15 
1.2 
Rationale ............................................................................................................................................ 17 
1.3 
BMMSCs.............................................................................................................................................. 24 
1.4 
BMMSC Preclinical Experience ................................................................................................. 24 
1.4.1 
MSCs in Cardiovascular Disorders ........................................................................................... 25 
1.4.2 
Allogeneic Mesenchymal Stem Cell Transplation Improves Global Cardiac 
Function in a Swine Model of Acute Myocardial Infarction ........................................... 26 
1.4.3 
MSCs in Graft-Versus-Host Disease (GVHD) ........................................................................ 26 
1.4.4 
MSCs in Pulmonary Disorders ................................................................................................... 27 
1.5 
BMMSC previous Experience in Humans .............................................................................. 27 
1.5.1 
Safety Information ......................................................................................................................... 28 
1.5.1.1 
MSCs Safety in Cardiac Disease ................................................................................................. 28 
1.5.1.2 
MSCs Safety in Graft Versus Host Disease (GVHD) ............................................................ 29 
1.5.1.3 
MSCs Safety in Pulmonary Disorders ..................................................................................... 29 
1.6 
Efficacy Information ...................................................................................................................... 29 
1.6.1 
MSCs Efficacy in Cardiac Disease ............................................................................................. 29 
1.6.2 
MSCs Efficacy in Graft Versus Host Disease (GVHD) ........................................................ 29 
1.6.3 
MSCs Efficacy in Pulmonary Disorders .................................................................................. 29 
1.6.4 
MSCs Efficacy in Endothelial Disorders and Metabolic Syndrome ............................. 29 
1.6.5 
Tabulated Previous Human Experience  ............................................................................... 29 
1.7 
Safety and Efficacy of Multiple Doses of MSCs .................................................................... 33 
1.8 
Pharmacology and Toxicology Studies of BMSC ................................................................ 34 
1.9 
UCMSCs ............................................................................................................................................... 37 
1.10 
UCMSCs: Preclinical Experience ............................................................................................... 38 
1.11 
UCMSCs: Previous Experience in Humans ............................................................................ 40 
1.12 
Pharmacology and Toxicology Studies of Mesenchymal Stem Cells .......................... 43 
2.  
STUDY OBJECTIVES AND ENDPOINTS................................................................................... 45 
2.1 
Study Objectives ............................................................................................................................. 45 

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2.1.1 
Primary Objective........................................................................................................................... 45 
2.1.2 
Secondary Objectives .................................................................................................................... 45 
2.2 
Study Endpoints .............................................................................................................................. 46 
2.2.1 
Primary Endpoints (Safety) ........................................................................................................ 46 
2.2.2. 
Secondary Endpoints (Efficacy)................................................................................................ 46 
3. 
STUDY DESIGN ................................................................................................................................ 46 
3.1 
Description of the Study .............................................................................................................. 46 
3.2. 
Randomization Study .................................................................................................................... 47 
4.  
SUBJECT SELECTION .................................................................................................................... 47 
4.1  
Inclusion Criteria ............................................................................................................................ 47 
4.2  
Exclusion Criteria ........................................................................................................................... 48 
4.3  
Concomitant Treatments, Procedures, and Nondrug Therapies ................................. 49 
4.4  
Withdrawal Criteria....................................................................................................................... 49 
5.   
MESENCHYMAL STEM CELL DONORS ................................................................................... 49 
5.1  
Bone Marrow Aspiration, cord tissue harvest, MSC culture for generation of MSCs 
and Placebo formulation. ............................................................................................................ 50 
5.2  
Donor Eligibility .............................................................................................................................. 51 
5.2.1 
Bone Marrow Donors Screening and Testing...................................................................... 51 
5.2.2 
Umbilical Cord Tissue Donor Screening and Testing ....................................................... 52 
5.3  
Bone Marrow Donor Consent .................................................................................................... 53 
5.4  
Follow-up Schedule for Bone Marrow Donors ................................................................... 54 
5.5 
Biomarker Assessment for Bone Marrow Donors ............................................................. 54 
6.  
TREATMENT OF SUBJECTS ........................................................................................................ 54 
6.1  
Study Investigational Product ................................................................................................... 54 
6.2  
Dosing ................................................................................................................................................. 54 
6.3  
Dosage Rationale ............................................................................................................................ 55 
6.4  
Administration Rate ...................................................................................................................... 55 
6.5  
Concomitant Therapy ................................................................................................................... 55 
6.5.1 
Permitted therapy .......................................................................................................................... 55 
6.5.2 
Excluded therapy ............................................................................................................................ 55 
6.5.3. 
Subject monitoring ........................................................................................................................ 55 
6.6 
Blinding and Un-blinding ............................................................................................................ 56 
6.7 
Study Investigational Therapy Management ....................................................................... 56 
6.7.1 
Investigational Product Labeling and Storage .................................................................... 56 

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6.7.2 
Investigational Product Accountability Procedures ......................................................... 56 
7. 
STUDY PROCEDURES .................................................................................................................... 57 
7.1. 
Time and Events Schedule .......................................................................................................... 57 
7.2.1 
Screening Visit ................................................................................................................................. 60 
7.2.2 
Baseline Visit .................................................................................................................................... 61 
7.2.3 
Day 0 Visit ......................................................................................................................................... 61 
7.2.4 
Week 2 Visit ...................................................................................................................................... 61 
7.2.5 
Month 1 Visit .................................................................................................................................... 61 
7.2.6 
Month 3 – Month 6 Visits............................................................................................................. 61 
7.2.7 
Month 12 Visit (Final Study Visit) ............................................................................................ 61 
7.3  
Assessment Details  ....................................................................................................................... 62 
7.3.1 
Physical Exam .................................................................................................................................. 68 
7.3.2 
Vital Signs .......................................................................................................................................... 68 
7.3.3 
Dobutamine Stress Echocardiography (DSE) ...................................................................... 69 
7.3.4 
Flow Mediated Diameter percent change (FMD%) .......................................................... 69 
7.3.5 
Laboratory Testing  ....................................................................................................................... 69 
8.   
SAFETY ............................................................................................................................................... 64 
8.1  
Safety Variables ............................................................................................................................... 64 
8.1.1  
Laboratory Evaluations................................................................................................................ 64 
8.1.2  
Pulse Oximetry ................................................................................................................................ 65 
8.1.3  
Pregnancy .......................................................................................................................................... 65 
8.1.4  
Determination of Infusional Toxicity...................................................................................... 65 
8.1.5  
Subject Stopping Guidelines ....................................................................................................... 66 
8.2 
Subject Observation and Discontinuation After IP Asministration ............................ 71 
8.3  
Definition of an Adverse Event ................................................................................................. 67 
8.4 
Definition of Adverse Reaction ................................................................................................. 68 
8.5 
Definition of Suspected Adverse Reaction ............................................................................ 68 
8.6 
Definition of Serious ...................................................................................................................... 68 
8.7 
Definition of Unexpected ............................................................................................................. 69 
8.8 
Clinical Laboratory Assessments and Other Abnormal Assessments as Adverse 
Events and Serious Adverse Events ........................................................................................ 69 
8.9 
Recording of Adverse Events and Serious Adverse Events ........................................... 69 
8.10 
Intensity of Adverse Events and Serious Adverse Events .............................................. 70 
8.11 
Causality of Adverse Events and Serious Adverse Events .............................................. 70 

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8.12 
Follow-Up of Adverse Events and Serious Adverse Events ........................................... 71 
8.13 
Timeframes for Submitting SAE Reports .............................................................................. 72 
8.14 
Post-Study Adverse Events and Serious Adverse Events ............................................... 72 
8.15 
Regulatory Aspects of Adverse Event Reporting ............................................................... 72 
9. 
STATISTICAL ANALYSIS .............................................................................................................. 73 
9.1  
Determination of Sample Size and Analysis Population ................................................. 73 
9.2  
General Statistical Methods ........................................................................................................ 73 
9.3 
Interim Analyses ............................................................................................................................. 74 
9.4  
Data Safety Monitoring Board (DSMB) .................................................................................. 74 
9.4.1.  
ROLE OF THE DSMB ...................................................................................................................... 74 
9.4.2.  
Purpose of the DSMB .................................................................................................................... 74 
9.4.2.1 
DSMB Membership ........................................................................................................................ 80 
9.4.2.2  
Financial Disclosures and Conflict of Interest ..................................................................... 74 
9.4.2.3 
DSMB Responsabilities................................................................................................................. 74 
9.4.2.4 
Confidentiality ................................................................................................................................. 81 
9.4.2.5  
Study Conduct and Termination............................................................................................... 82 
9.4.2.6 
Investigator Responsabilities .................................................................................................... 82 
9.4.3.  
Committee Meetings ..................................................................................................................... 82 
9.4.3.1  
Organizational Meeting ................................................................................................................ 82 
9.4.3.2  
Review of Periodic Safety Update Reports ........................................................................... 82 
9.4.3.3  
Data Review Meetings .................................................................................................................. 83 
9.4.4  
Data Flow ........................................................................................................................................... 79 
9.4.4.1  
Communications and Reports ................................................................................................... 85 
9.4.4.2  
Review of Unblinding Requests  ............................................................................................... 85 
9.4.4.3  
DSMB Additional Analysis Requests ....................................................................................... 85 
9.4.4.4  
Confidentiality ................................................................................................................................. 85 
9.4.5  
Communication ............................................................................................................................... 80 
9.4.5.1  
DSMB Minutes ................................................................................................................................. 86 
9.4.5.2  
DSMB Recomendations ................................................................................................................ 86 
 
10.  
STUDY ADMINISTRATION .......................................................................................................... 81 
10.1 
Regulatory Authority Approval ................................................................................................ 81 

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10.2  
Ethics Approval ............................................................................................................................... 81 
10.3  
Subject Informed Consent ........................................................................................................... 81 
10.4  
Confidentiality of Information................................................................................................... 82 
10.5  
Payments to Subjects .................................................................................................................... 83 
10.6  
Payments to Donors ...................................................................................................................... 83 
APPENDIX 1:  
Infusion Guidelines ......................................................................................................... 84 
APPENDIX 2:        Dobutamine Stress Echo (DSE) Instructions ........................................................ 87 
APPENDIX 3:        Flow Mediated Diameter Percent Change (FMD%) Instrucions  ................. 94 
 
 
 

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Authorship Team (alphabetical order) 
 
The following individuals provided substantial input during protocol development: 
 
Lina V. Caceres, MHS  
 
University of Miami 
 
Moisaniel DaFonseca 
 
University of Miami 
 
Darcy L. DiFede, RN, BSN 
 
University of Miami 
 
Joshua M. Hare, MD*  
 
University of Miami 
 
Aisha Khan, MSc, MBA 
 
University of Miami  
 
Bangon Longsomboon, MA  
University of Miami 
 
Marietsy V. Pujol, MBA 
 
University of Miami 
 
Kevin N. Ramdas, MD, MPH  
University of Miami 
 
Ivonne H. Schulman, MD 
 
University of Miami 
 
 
* Principal investigator 
 
 
 
 
 
 
 
 

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List of Abbreviations 
6MWT 
6 Minute Walk Test 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BM 
Bone Marrow 
BMMSCs 
Bone Marrow Mesenchymal Stem Cells 
BNP 
Brain Natriuretic Peptide 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulations 
CFU-F 
Colony-Forming Unit in Fibroblastic 
CMP 
Cell Manufacturing Program 
CMV 
Cytomegalovirus antibody 
COPD 
Chronic Obstructive Pulmonary Disease 
CPL 
Cell Processing Laboratory  
CRC 
Clinical Research Center 
CRF 
Case Report Form  
CRP 
C-Reactive Protein 
CRO 
Contract Research Organization 
CSF 
Colony Stimulating Factor 
CT 
Computed Tomography 
CVD 
Cardiovascular Disease 
DMARD 
Disease Modifying Anti-Rheumatic Drugs 
DMSO 
Dimethyl Sulfoxide 
DSE 
Dobutamine Stress Echocardiogram  
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram  
EDTA 
Ethylenediaminetetraacetic Acid 
EDV 
End Diastolic Volume 
EPC 
Endothelial progenitor cells 
ESV 
End Systolic Volume 
FACS 
Flow Cytometry 
FDA 
Food and Drug Administration 
FEV-1 
Forced Expiratory Volume 
FMD 
Flow Mediated Diameter  
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 
GFP 
Green fluorescent protein 
GIT 
Gastrointestinal Tract 
GMP 
Good Manufacturing Practices 
GVHD 
Graft Versus Host Disease 

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HARP 
Harmonic Phase 
HBcAb 
Hepatitis B Core Antibody 
HBsAg 
Hepatitis B Surface Antigen 
HC 
Hemorrhagic Cystitis  
HCVAb 
Hepatitis C Virus antibody 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
HLA 
Human Leukocyte Antigen 
HMWF 
High Molecular Weight Fraction 
HSC 
Hematopoietic Stem Cells 
HTLV 
Human T-Lymphotropic Virus 
hUC 
Human Umbilical Cord Tissue 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization (of Technical 
Requirements of pharmaceuticals for Human Use) 
ICR 
Imprinting Control Region mouse 
IEC 
Independent Ethics Committee 
IIEF 
International Index of Erectile Function Questionnaire 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
IP 
Investigational Product 
IRB  
Institutional Review Board  
ISCI 
Interdisciplinary Stem Cell Institute 
IUD 
Intrauterine Device  
IV 
Intravenous 
LAD 
Left Anterior Descending 
LFTs 
Liver Function Tests 
LV 
Left Ventricular function 
MI 
Myocardial Infarction 
MNC 
Mononuclear Cell 
MRI 
Magnetic Resonance Imaging  
MSC 
Mesenchymal Stem Cells 
NMDP 
National Marrow Donor Program 
PBMC 
Peripheral Blood Mononuclear Cells 
PSURs 
Periodic Safety Update Reports 
QOL 
Quality of Life Questionnaires 
RNA 
Ribonucleic Acid 
RPMS 
Relapsing Remitting Multiple Sclerosis 
RPR 
Rapid Plasma Reagin 
SAE 
Serious Adverse Events 
SAO2 
Oxygen Saturation 
SAP 
Statistical Analysis Plan 
SCF 
Stem Cell Factor Antigen 
SF-36 
Short Form – 36  

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SLE 
Systemic Lupus Erythematosus 
SLEDAI 
Systemic Lupus Erythematosus Disease Activity Index 
SQOL-F 
Sexual Quality of Life - Female 
SW  
Stroke Work 
TE-SAE 
Treatment Emergent Serious Adverse Events 
TNFα 
Tumor Necrosis Factor-alpha  
TTC 
Triphenyltetrazolium chloride 
UC 
Umbilical Cord Tissue 
UCMSCs 
Umbilical Cord Tissue derived Mesenchymal Stem Cells 
VEGFR2 
Vascular endothelial growth factor receptor-2 
VO2 
Oxygen Consumption  
VDRL 
Venereal Disease Research Laboratory test 
WBC 
White Blood Count 
WJ 
Wharton’s Jelly 
 
 

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Protocol Synopsis 
Sponsor:  Interdisciplinary Stem Cell Institute (ISCI) at the University of Miami Miller 
School of Medicine 
Name of Study Therapy: Allogeneic Umbilical Cord Tissue derived MSCs (UCMSCs) 
versus Bone Marrow derived Mesenchymal Stem Cells (BMMSCs) 
Title of Study: A Phase I/II, Randomized, Blinded, Placebo-controlled Comparative 
study to evaluate the Safety and Potential Efficacy of Intravenous Infusion of Umbilical 
Cord Tissue (UC) derived Mesenchymal Stem Cells (MSCs) Versus Bone Marrow (BM) 
derived MSCs to evaluate cytokine suppression in patients with chronic inflammation 
due to Metabolic Syndrome. The CERES Trial. 
Study Center: ISCI at the University of Miami 
Miller School of Medicine  
Phase of Development: Phase I/II 
Objectives:   
Primary: To compare the safety of UCMSCs and BMMSCs administered intravenously in 
patients with chronic inflammation due to Metabolic Syndrome.  
Secondary:  
- 
To demonstrate the efficacy of UCMSCs and BMMSCs administered intravenously in 
patients with chronic inflammation due to Metabolic Syndrome as assessed by (see 
Table 9 in Section 2.2.2): 
- 
symptom related quality of life  
- 
cardiovascular status  
- 
inflammatory cytokines 
- 
endothelial function 
- 
lipid profile 
- 
glucose homeostasis 
- 
1year survival 
Design and Investigational Plan:  This Study is intended as a safety assessment prior to 
a full comparator study.  In this Study, cells administered via intravenous infusion (IV) will 
be tested in 42 patients in two phases (Pilot and Randomized): 
 
Pilot Phase (12 subjects) 
Group 1 (3 subjects) 
Three (3) subjects will be treated with a single administration of 2 x 107 (20 million) 
UCMSCs delivered via peripheral intravenous infusion. 
Group 2 (3 subjects) 
Three (3) subjects will be treated with a single IV administration of 2 x 107 (20 million) 
BMMSCs delivered via peripheral intravenous infusion. 
The subjects in the high dose (Groups 3 & 4) will not be treated until the subjects in the 
low dose (Groups 1 & 2) have completed their one-month follow-up assessments and 
safety measures have been reviewed to confirm that there have been no treatment 
emergent SAE’s.  

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Group 3 (3 subjects) 
Three (3) subjects will be treated with a single IV administration of 1 x 108 (100 million) 
UCMSCs delivered via peripheral intravenous infusion. 
 
Group 4 (3 subjects) 
Three (3) subjects will be treated with a single IV administration of 1 x 108 (100 million) 
BMMSCs delivered via peripheral intravenous infusion. 
 
Randomized Phase (30 subjects) 
 
Group A (10 subjects – UCMSCs) 
Ten (10) subjects will be treated with a single administration of 1 x 108 (100 million) 
UCMSCs delivered via peripheral intravenous infusion.  
Group B (10subjects – BMMSCs) 
Ten (10) subjects will be treated with a single administration of 1 x 108 (100 million) 
BMMSC delivered via peripheral intravenous infusion. 
Group C (10 subjects – Placebo) 
Ten (10) subjects will be treated with a single administration of placebo delivered via 
peripheral intravenous infusion. 
 
Subjects in each pilot phase group (Group 1, 2, 3 and 4) will not be treated less than 5 days 
apart. 
The randomized portion of the study will be conducted after a full review of the safety 
data from the Pilot Phase by the DSMB 
 
Patients will be randomized in a 1:1:1: ratio to one of the 3 groups in the randomized 
phase. For subjects randomized to B (BMMSCs); the cells will be derived from a healthy 
allogeneic bone marrow donor (obtained by iliac crest aspiration).  
For subjects randomized to Group A (UCMSCs); the cells will be derived from a healthy 
allogeneic umbilical cord tissue donor.  
Route of Administration 
Peripheral Intravenous Infusion 
Duration of Study 
Participation 
12 months (Follow-up will be at 2 weeks, 1 Month, 3, 6, and 
12 months.) 
Inclusion Criteria 
 
1. Provide written informed consent 
2. Subjects age > 21 and < 95 years at the time of signing 
the Informed Consent Form. 
3. Each subject must have endothelial dysfunction. 
Endothelial dysfunction Criteria: 

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Impaired flow-mediated vasodilation (FMD <7%) 
4. At the time of enrollment, each subject must meet at 
least 3 out of the 5 criteria under the harmonized 
definition of the metabolic syndrome, consisting of the 
following: 
 
Waist circumference - US defined:  ≥ 102 cm (males) 
                                                              or ≥ 88 cm (females) 
Elevated triglycerides - ≥ 150 mg/dL (1.7 mM) 
 
Reduced HDL-C -           Males:  <40 mg/dL (1.0 mM) 
                                        Females:  <50 mg/dL (1.3 mM)  
Elevated blood pressure - Systolic ≥ 130 mm Hg and/or 
                                                   Diastolic ≥ 85 mm Hg 
 
Elevated fasting glucose - ≥ 100 mg/dL 
See Table 10 in section 4.1 for more details.  
Exclusion Criteria 
1. Be a female who is pregnant, nursing, or of 
childbearing potential while not practicing effective 
contraceptive 
methods. 
Female 
subjects 
must 
undergo a blood or urine pregnancy test at screening 
and within 36 hours prior to infusion. 
2. Inability to perform any of the assessments required 
for endpoint analysis. 
3. Active listing (or expected future listing) for 
transplant of any organ. 
4. Clinically important abnormal screening laboratory 
values. (Please reference Section 4.2 for more 
details) 
5. Serious comorbid illness or any other condition that, 
in the opinion of the investigator, may compromise 
the safety or compliance of the subject or preclude 
successful completion of the study. (Please reference 
Section 4.2 for more details) 
6. Have known allergies to penicillin or streptomycin.  
7. Be a solid organ transplant recipient. This does not 
include prior cell based therapy (>12 months prior 
to enrollment), bone, skin, ligament, tendon or 
corneal grafting. Have a history of organ or cell 
transplant rejection. 
8. Have a clinical history of malignancy within 3 years 
(i.e., subjects with prior malignancy must be disease 

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free for 3 years), except curatively-treated basal cell 
carcinoma, squamous cell carcinoma, melanoma in 
situ or cervical carcinoma, if recurrence occurs. 
9. Have a non-pulmonary condition that limits lifespan 
to < 1 year.  
10. History of drug abuse (illegal “street” drugs except 
marijuana, or prescription medications not being 
used appropriately for a pre-existing medical 
condition) or alcohol abuse (≥ 5 drinks/day for ˃ 3 
months), or documented medical, occupational, or 
legal problems arising from the use of alcohol or 
drugs within the past 24 months  
11. Be serum positive for HIV, hepatitis BsAg or Viremic 
hepatitis C, and/or Syphilis – VDRL (If VDRL is 
reactive Confirmation with FTA-ABS is needed 
(Syphilis)). 
12. Be currently participating (or participated within the 
previous 30 days) in an investigational therapeutic 
or device trial. 
13. Patients with EF<45% (heart failure patients). 
14. GFR < 35 (chronic kidney disease stage 3 or higher). 
15. Liver disease (elevated LFTs greater than 3x upper 
limit of normal). 
16. Advanced pulmonary disease (requiring home 
oxygen and/or less than 1 year expected life span). 
17. Proliferative diabetic retinopathy  
18. Hemoglobin A1C greater than 7. 
 

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1. 
INTRODUCTION 
 
1.1 
Background 
The metabolic syndrome is a group of risk factors that increases chances for developing 
cardiovascular disease (CVD), Type II diabetes mellitus (T2DM), and all-cause mortality by 
promoting a pro-inflammatory state coupled with endothelial dysfunction1. 
The metabolic syndrome is a defined condition under the WHO International Classification 
of Disease (ICD-9) code (277.7), and is also known as X syndrome, insulin resistance 
syndrome, cardiometabolic syndrome, and Reaven's syndrome. The precise definition of 
the metabolic syndrome has evolved over the past few decades, with definitions 
historically differing slightly depending upon the health organization1,2. To resolve this, a 
multi-organizational harmonized definition of the metabolic syndrome has been reached 
by the National Heart, Lung, and Blood Institute; the International Diabetes Federation 
Task Force on Epidemiology and Prevention; the American Heart Association; the World 
Heart Federation; the International Atherosclerosis Society; and the International 
Association for the Study of Obesity3. Specifically, the metabolic syndrome is defined as a 
cluster of risk factors for CVD and T2DM, with these risk factors consisting of hypertension, 
dyslipidemia via raised triglycerides, dyslipidemia via lowered high-density lipoprotein 
(HDL), fasting hyperglycemia/dysglycemia (impaired glucose tolerance; insulin resistance), 
and central obesity (apple-shaped adiposity) (Table 1). None of these risk factors is 
obligatory, but a patient having any 3 of the 5 risk factors is defined as having the metabolic 
syndrome. Although the first four criteria are highly agreed upon, some controversy still 
exist on exactly how to define abdominal obesity, and whether it should be included as an 
obligatory risk factor4. 
Table 1. Criteria for the Metabolic Syndrome 
Measure 
Categorical Cut-Off Points 
Alternative Indicators 
Waist circumference US defined:  ≥ 102 cm (males) 
or ≥ 88 cm (females) 
Ethnic and country-specific 
definitions 
Elevated triglycerides ≥ 150 mg/dL (1.7 mM) 
Drug treatment for elevated 
triglycerides 
Reduced HDL 
Males:  <40 mg/dL (1.0 mM) 
Females:  <50 mg/dL (1.3 mM) 
Drug treatment for reduced 
HDL-C 
Elevated blood 
pressure 
Systolic ≥ 130 mm Hg and/or 
Diastolic ≥ 85 mm Hg 
Antihypertensive drug 
treatment for a history of 
hypertension 
Elevated fasting 
glucose 
≥ 100 mg/dL 
Drug treatment of elevated 
glucose 
 

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Patients with the metabolic syndrome have double the risk of developing CVD in 5 – 10 
years versus normal individuals, and a 5-fold increased risk of developing T2DM1,3,5. 
Furthermore, compared to individuals without the syndrome, patients with the metabolic 
syndrome are 2 to 4- times more likely to have a stroke, 3 to 4-times more likely to have a 
myocardial infarction (MI), and 2-times more likely to die from any such an event5,6. The 
incidence of the metabolic syndrome has reached epidemic proportions worldwide, with 
>40% of US adults ≥20 years of age classified as having the metabolic syndrome3,7. Thus, 
effective treatment of the metabolic syndrome is a paramount health concern. 
Inflammation caused by the Metabolic Syndrome 
Dysregulated inflammation is a considerable key physiological correlate of the metabolic 
syndrome, in which affected persons commonly manifest a proinflammatory and 
prothrombotic  
state8. Inflammatory markers are predictors of cardiovascular events and progression to 
diabetes in healthy individuals, including individuals with metabolic syndrome. For 
example, those with metabolic syndrome are more likely to have elevated C-reactive 
protein (CRP), fibrinogen, interleukin-6 (IL-6), red blood cell distribution width (RDW) and 
D-dimer8. 
Excess adiposity promotes the metabolic syndrome in a least 2 major ways8,9. First, the 
adipose cells release adipose tissue-derived non-esterified fatty acids (NEFAs) that inhibit 
insulin signaling10. Second, the increased adipose cells (especially abdominal) releases 
adipokines, which are cytokines that promote a pro-inflammatory state11. These promote 
diminished whole-body sensitivity to insulin. Consequently, the pancreas initially increases 
insulin secretion to maintain normoglycemia. The result is a somewhat asymptomatic 
phase which can last many years, but which nevertheless leads to the development of a 
pro-inflammatory 
and 
pro-thrombotic 
state 
accompanied by 
dyslipidemia 
and 
hypertension, and eventually the co-morbidities that include T2DM and CVD. 
Endothelial Dysfunction, Endothelial Progenitor Cells, and the Metabolic Syndrome 
The presence of the metabolic syndrome is associated with advanced vascular damage6 and 
endothelial 
dysfunction12,13. 
Endothelial 
dysfunction 
is 
characterized 
by 
a 
pathophysiological shift in endothelial functioning towards a state that is proinflammatory, 
prothrombic, and of reduced flow-mediated vasodilation (FMD)14,15,16,17. Endothelial 
dysfunction is commonly accepted to be the earliest manifestations of atherosclerosis, 
insulin resistance, and diabetes15,17, and is a crucial component of the pathophysiology of 
numerous cardiovascular (CV) disorders, including heart failure (HF)18,19. These 
pathological changes begin with damage to the endothelium, in which production of the 
vasodilator, nitric oxide (NO), becomes substantially impaired, and the production of 
reactive oxygen species (ROS) increases20,21. Nitric oxide is also thought to inhibit cellular 
pathways involved in inflammation and thrombosis22. Since such pathological changes 
begin with damage to the endothelium, targeting endothelial dysfunction could provide a 
general therapeutic approach to treat the metabolic syndrome. Endothelial dysfunction and 
the metabolic syndrome are also characterized by reduced functioning of endothelial 

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progenitor cell (EPC)23,24,25,26,27. In fact, the metabolic syndrome is characterized by a 
decrease in circulating endothelial progenitor cells (EPCs), regardless of whether a patient 
displays T2DM or CVD24. EPCs are bone marrow-derived progenitor cells 
Several clinical trials and research work have been done to prove that Mesenchymal Stem 
Cells (MSCs) derived from bone marrow or the umbilical cord tissue have anti-
inflammatory properties and these cells inhibit T cells proliferation and suppress 
allogeneic T-cell response. The main features of the T cell response are cell proliferation 
and cytokines secretion. Inhibition of T cell proliferation is one of the most significant 
effects for MSCs. In vitro, MSCs are capable of suppressing T lymphocyte proliferation 
induced by mitogens, alloantigens, as well as activation of T cells by CD3 and CD28 
antibodies24,28,29,30,31,32,33. Suppression of T cell proliferation by MSCs has no immunological 
restriction, similar suppressive effects being observed with cells that were autologous or 
allogeneic to the responder cells.  
The hypothesis of this trial is that suppressing cytokines levels in subjects with metabolic 
syndrome will cause a decrease in the chronic inflammation and endothelial dysfunction 
caused by the disease34,35,36,37,38.  
1.2 
Rationale 
We have analyzed TNFα levels for our subjects for the CRATUS Study, allogeneic BMMSCs 
were tested in a range of 20M MSCs to 200M MSCs in a Phase 1/2 clinical study in 45 Aging 
Frailty subjects (BB-IND#15679).  The study contained a run in pilot phase testing single 
intravenous administration of 20M, 100M or 200M MSCs, followed by a randomized, 
placebo-controlled double blind Phase 2 single intravenous administration of 100M MSC or 
200M MSCs or placebo in 30 subjects. Results showed no significant changes in any of the 
treatment arms.  However, the average baseline TNFα levels for the subjects in all 3 arms 
were less than half those in the Phase 1 study, and were already close to the low level for 
the reference range (1.2 – 15.3 pg/mL).  No significant changes in other biomarkers were 
observed. 
As we know that frailty is hypothesized to result from a complex interplay of biochemical 
and multi-systemic changes that may result in decreased physiologic reserves in older 
adults and biological mechanism that underlies the decline in physical function associated 
with aging frailty is chronic inflammation35.  This response is initially characterized by a 
local release of cytokines, responsible for the amplification and regulation of the 
inflammatory cascade.   
Cytokines are also involved in numerous physiological functions, such as muscle and bone 
tissues turnover, immunoregulation, and hematopoiesis and their circulating levels have 
been related to several disease processes, primarily atherosclerosis and cardiovascular 
disease. Chronically elevated inflammatory biomarkers have been observed in the presence 
of acute and chronic conditions, including atherosclerosis, Parkinson’s disease, type 2 
diabetes mellitus, sarcopenia, functional disability, cerebrovascular disease, coronary heart 
disease, CHF and arthritis.   Inflammation exerts detrimental effects on muscle, bone, 
cardiac function, hematopoiesis and cognition34,39,40.    

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Not surprisingly, data from our frailty studies indicate an association between the frailty 
syndrome and elevated levels of pro-inflammatory mediators including IL-6, C-reactive 
protein (CRP), and TNFα41,41,42,42,43,43.   Although these various inflammatory markers are 
correlated with each other, the relative importance of these markers as predictors of frailty 
or physical decline has not been established.      
While this current study will include assessment of a panel of cytokines, there is particular 
interest in TNFα due to evidence that I.V. infusion of allogeneic MSCs significantly 
decreases serum TNFα levels in aging frailty subjects.    
In our frailty study, cytokine levels were measured at baseline, and at 6 months after 
treatment with I.V. allogeneic MSCs, the intervention proposed to be tested in the current 
clinical trial.  Minimal effect was noted on IL-6 and CRP, but TNFα, which was elevated at 
baseline, decreased significantly in both the open label and randomized phases of the 
study.   In Phase 1, mean baseline TNFα levels were 4.14 ± 2.0 pg/ml, 5.30 ± 0.94, and 5.88 
± 1.12 for the 20 million MSC, 100 million MSC and 200 million MSC frail subject groups, 
respectively.  These levels were consistent with, if not slightly higher, than the frail (3.19 
±2.68 pg/ml) and dependent (4.58 ± 3.30 pg/ml) groups in Hubbard et al44, and the frail 
group (2.11 pg/ml) in Serviddio et al45.   Treatment with allogeneic MSCs resulted in all 3 of 
the Phase 1 cohorts showing a statistically significant reduction in mean TNFα (Figure 1). 
Figure 1:  TNFα levels decreased with allogeneic MSC treatment.  Serum levels decreased 
over 50% at 6-months after infusion with allogeneic MSCs.  p-values are for within 
treatment arm versus baseline. 
In Phase 2 of the CRATUS study, mean baseline TNFα was 3.14 ± 0.37 pg/ml, 3.33 ± 0.52, 
and 2.35 ± 0.43 for the 100 million MSC, 200 million MSC, and placebo groups, respectively.  
Six months following I.V. infusion with allogeneic MSCs, TNFα decreased in all cohorts, 
including placebo, however the 100 million MSC group showed significant reductions 
relative to baseline. (Figure 2) 
  
 
 

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Figure 2:  Serum TNFα levels from Phase 2 randomized portion of the CRATUS study in 
frailty.  TNFα levels were elevated at baseline (BL), and a significant reduction after i.v. 
infusion of 100M MSCs was observed.   Plotted are averages and SEM, using only subject 
data for which there was both baseline and 6-month data.  p-values are within group 
versus baseline. 
Figure 2. Serum TNFα levels 
 
  
  
 
.   
 
Results from the CHS established a strong association between the presence of clinically 
manifest cardiovascular disease (CVD) and subclinical cardiovascular abnormalities, with 
frailty syndrome46.   In the Health ABC Study, high levels of circulating TNFα were shown to 
be predictive of CVD (CHD, stroke and CHF) in older adults 70-79 years of age with no 
evidence of CVD at baseline46.  The same group reported a significant association between 
several inflammatory markers and the syndrome of frailty in the absence of CVD and 
diabetes44, supporting the hypothesis that age-related inflammation system changes may 
underlie the development of both the clinical criteria of frailty and the physiological 
vulnerability observed in frail older adults.  However, this does not rule out the possibility 
of chronic inflammation due to subclinical disease such as atherosclerosis, and associated 
reduction in end organ functional reserve, which is thought to be part of the underlying 
pathophysiology that is recognized clinically as frailty47.   While a disease-independent 
inflammatory mechanism for frailty is possible, subclinical versions of CVD and/or diabetes 
may have a greater influence on the development of frailty than previously suspected. 
Clinical Restoration of Endothelial Dysfunction Using MSC Therapy 
Endothelial dysfunction is a critical pathophysiological component of numerous 
cardiovascular disorders, and presents in patients with hypertension, atherosclerosis, and 
diabetes mellitus18,19,48. Furthermore, circulating EPC levels and bioactivity are diminished 
in patients with heart failure49. 
The pro-angiogenic properties of MSCs make them attractive as a potential therapeutic for 
restoring endothelial function50. This may be due to the capacity of MSCs to differentiate 

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not only into cells of mesodermal origin, but into cells of endodermal and ectodermal 
origin51, as well as their ability to stimulate endogenous progenitor cells52,53. Given these 
properties of MSCs, the hypothesis was tested that MSCs could stimulate the bioactivity of 
circulating EPCs and improve endothelial function in patients with heart failure54. 
Specifically, the therapeutic capabilities of both autologous and allogeneic MSCs were 
tested for the ability to stimulate EPC function and augment vascular relaxation in patients 
with heart failure due to either idiopathic dilated cardiomyopathy (DCM) or ischemic 
cardiomyopathy (ICM)55. These IRB-approved studies used heart failure patients enrolled 
in POSEIDON-DCM (NCT01392625), “A Phase I/II, Randomized Pilot Study of the 
Comparative Safety and Efficacy of Transendocardial Injection of Autologous Mesenchymal 
Stem Cells Versus Allogeneic Mesenchymal Stem Cells in Patients with Nonischemic Dilated 
Cardiomyopathy”56 and in TRIDENT (NCT02013674), “The Transendocardial Stem Cell 
Injection Delivery Effects on Neomyogenesis Study”. 
The results of these studies provided insight leading to the discovery that allogeneic MSCs 
significantly improved endothelial dysfunction in heart failure patients. This was due to the 
improvement of EPC bioactivity and endothelial function, regardless of the etiology of the 
heart failure. Surprisingly, though, autologous MSCs did not confer similar beneficial 
effects. 
The number of circulating endothelial progenitor cells can be assessed using an endothelial 
progenitor cell-colony forming unit (EPC-CFU) assay: the more EPC-CFUs that form, the 
greater the number of circulating EPCs. It was found that treatment of heart failure patients 
with allogeneic human MSCs significantly improved the number of circulating EPCs at 3 
months after infusion (Figure 3). In surprising contrast, however, autologous MSCs did not 
provide significant improvement in the number of circulating EPCs. 

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Similarly, allogeneic human MSCs significantly increased flow-mediated vasodilation 
(FMD) in heart failure patients at 3 months after infusion, demonstrating improved 
endothelial function (Figure 4). Again, autologous MSCs did not confer significant 
improvement. More importantly, when assessed at an individual patient level, every 
subject with idiopathic dilated cardiomyopathy who received allogeneic human MSCs had 
improved FMD, whereas the majority of subjects receiving autologous MSCs showed either 
no improvement or worsening. Furthermore, the improvement in FMD directly correlated 
with the improvement in circulating EPC number. 
Allogeneic MSCs 
Autologous MSCs 
Figure 3.  Allogeneic MSCs, but not autologous MSCs, improve EPC colony forming units in heart 
failure patients. A, Patients treated with allogeneic MSCs had a significant improvement in endothelial
progenitor cell-colony forming units (EPC-CFUs) at 3 months post-treatment (n= 15, *P < 0. 0001, t-
test). B, Patients treated with autologous MSCs had no change in EPC-CFUs post-treatment (n=7,
P=NS, t-test). 

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At 3 months’ post-infusion, subjects who received allogeneic human MSCs also had 
significantly suppressed serum levels of vascular endothelium growth factor (VEGF) 
relative to their baseline levels (Figure 5). In fact, the levels of VEGF approached those of 
normal, healthy (control) subjects. In contrast, autologous MSCs actually led to a significant 
increase VEGF levels at 3 months. Furthermore, both the absolute levels of VEGF, and the 
relative changes in VEGF, had an inverse correlation to the number of EPC-CFUs. It should 
be noted that serum level of VEGF was too low to detect in the majority of the control 
subjects. 
Allogeneic MSCs 
Autologous MSCs 
Figure 4.  Allogeneic MSCs, but not autologous MSCs, improve flow-mediated vasodilation (FMD) in 
heart failure patients. A, Patients treated with allogeneic MSCs had an increase in FMD% at 3 months’
post-injection (n=15, *P=0.0002, t-test). B, Patients treated with autologous MSCs had no significant
difference in FMD% at 3 months’ post-injection (n= 7, P=NS, t-test). C, A strong correlation existed
between the absolute change in FMD% and the absolute change in EPC-CFUs from baseline to 3

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In summary, this study demonstrated the potent and clinically relevant efficacy of 
allogeneic MSCs to treat endothelial dysfunction after heart failure. Specifically, allogeneic 
MSC therapy could restore flow-mediated vasodilation, EPC bioactivity, and VEGF levels 
towards normal. Furthermore, the insights gained in efficacy to treat endothelial 
dysfunction after heart failure implies that allogeneic MSC therapy may provide a generally 
useful therapy for treating all disorders associated with endothelial dysfunction.  
Allogeneic 
Autologous 
Figure 5. Allogeneic MSCs, but not autologous MSCs, improve serum VEGF levels. A, Patients (n=14) 
have a higher level of circulating VEGF compared to controls (n=9) at baseline (*P=0.0009, t-test; within-
group, P=0.21, P<0.001, respectively, D'Agostino-Pearson omnibus normality test). B, Patients who
received allogeneic MSCs (n=9) had a decrease in VEGF serum levels post-injection (Δ-547.5 ± 350.8
pg/mL, †P=0.0015, t-test; within-group P=0.96, D'Agostino-Pearson omnibus normality test), while
patients who received autologous MSCs (n=5) had increased serum VEGF post-injection
(Δ814.1±875.8), and there was a difference between the groups (†P=0.0012, t-test). C, There is an
inverse correlation between endothelial progenitor cell-colony forming units (EPC-CFUs) and serum
VEGF in patients at both baseline and 3months post-MSC treatment (R=−0.421, ‡P=0.026, Pearson
correlation). D, The change in EPC-CFUs from baseline to 3 months post-treatment strongly correlated

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Cells derived from adult bone marrow 
Bone marrow harbors a variety of cells that may contribute to vasculogenesis or 
cardiomyogenesis, either directly, or by facilitating endogenous repair mechanisms.  Bone 
marrow cells have been prepared on the basis of being 1.) endothelial precursor cells that 
are CD34+, 2.) MSCs purified without an antigen panning technique on the basis of their 
fibroblast morphology, ability to divide in culture and to differentiate into mesodermal 
lineages57, and 3.) cells that express stem cell factor receptor, c-Kit58,59.  Endothelial 
progenitor cells (EPCs) express the surface markers CD34, CD133, c-kit, and the vascular 
endothelial growth factor receptor-2 (VEGFR2; KDR; Flk-1)60,61,62,63,64,65.  Hematopoietic 
stem cells (HSCs) exhibit self-renewal and differentiation.  Their cell-surface phenotype is 
CD34+, stem cell factor antigen (SCF-1)+, c-kit+, and Lin-66.  While there has been 
controversy regarding the ability of bone marrow-derived cells to transdifferentiate into 
cardiomyocytes67, clinical trials of bone marrow therapies continue to suggest potential 
benefit in terms of improving a subject’s well-being and quality of life.   
 
1.3 
BMMSCs  
MSCs are multipotent cells capable of differentiating into a number of different cell lines.  
Because of their unique combination of multipotency, migratory ability, and 
immunoprivileged state (MSCs do not express major histocompatibility factor-II making 
allogeneic transplant possible)68, interest has abounded regarding their potential 
therapeutic and regenerative applications.  In fact, MSCs have been shown to hold promise 
as a novel therapeutic agent in multiple disease processes.  Treatment with MSCs has been 
shown to ameliorate severe graft versus host disease68, contribute to pancreatic islet and 
renal glomerular repair in diabetes69, attenuate sepsis70, reverse fulminant hepatic 
failure71, protect against ischemic acute renal failure72, reverse remodeling73,74,75 and 
improve cardiac function after myocardial infarction76, to be a potential source of multiple 
cell types for use in tissue engineering77,78, and to be capable of tissue regeneration after 
spinal cord trauma, stroke, and connective tissue injury79,80,81.   
In the lung, MSCs have been shown to contribute to tissue regeneration after elastase-
induced emphysema82, home to sites of asbestos induced lung injury83, contribute to tissue 
remodeling in a rat monocrotaline model of pulmonary hypertension84, decrease chronic 
airway inflammation in a murine ovalbumin model of asthma85, and to restore alveolar 
fluid balance after endotoxin induced acute lung injury86. 
Tracking of radioactively labeled cells shows that when administered intravenously, MSCs 
localize primarily to the lung, followed by the liver, and then other organs87.  A number of 
studies show that MSCs preferentially hone to sites of injury in the lung and contribute to 
tissue regeneration and repair88,89,90,91,92,93,94.  Using Y-chromosome fluorescence in-situ 
hybridization, Y-chromosome positive male MSCs can be found at sites of lung injury in 
transplanted female mice89,90,93.  These male MSCs appear to adopt anepithelial cell 
morphology, suggesting that they contribute to tissue regeneration either by fusion with 
resident epithelial cells or by mesenchymal to epithelial transition89.   
1.4 
BMMSC Preclinical Experience 
 

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Several cell-based therapies’ results propose that infusion of mesenchymal stem cells is a 
safe and novel approach believed to be an effective strategy to produce cytokine 
suppression in patients with chronic inflammation.  Below we review the impact of MSCs 
on the cardiovascular system following injury; this provides support for the impact of MSCs 
on cytokine suppression.  
1.4.1 MSCs in Cardiovascular Disorders 
 
Much work has been done on animal models that demonstrate both the safety and efficacy 
of MSCs to treat and repair cardiovascular damage. For example, therapeutic MSCs improve 
cardiac function in the rat model of dilated cardiomyopathy85, and repair the scarred 
myocardium and reverse remodeling after myocardial infarct in mice47,48,86. 
 
1.4.2 Allogeneic mesenchymal stem cell transplantation improves global cardiac 
function in a swine model of acute myocardial infarction: 
 
The porcine model is an excellent model in which to study cardiac damage and repair 
because of the anatomical similarity to the human heart. It was initially shown that 
transplantation of autologous MSCs into swine after myocardial infarct (MI) improved 
cardiac function87. This was supported by histological evidence at 8 weeks post-MI, which 
revealed differentiation of autologous MSCs into a myocyte-like phenotype. 
 
Because of the immune privileged nature of MSCs, we have performed a series of elegant 
experiments using transplantation of allogenic MSCs after porcine anterior MI, and 
demonstrated the safety and efficacy in repairing cardiac repair using hemodynamic 
analysis, imaging, and histological analyses. These experiments fell into two groups: the 
early treatment of acute myocardial infarction, and the treatment of chronic ischemic 
cardiomyopathy. 
 
In a randomized study, swine received a single injection of either 2 x 108 allogenic MSCs or 
placebo (n = 7 for each) at 3 days following MI88. The allogenic MSCs were delivered via 
transendocardial injection using the BioCardia Helical Infusion Catheter (BioCardia, Inc.), 
and all the animals tolerated the catheter-based injection well. The swine were assessed on 
a weekly basis for 8 weeks for hemodynamics and ventricular architecture. It was found 
that MSC injection produced a wide range of benefits, including improved regional and 
global ventricular function, reduced myocyte apoptosis, and improved tissue perfusion. 
Over a 2-3 month period, animals that received MSC exhibited a remarkable pattern of LV 
recovery marked by a substantial increase in stroke work (SW) and a return to normal of 
LV end diastolic pressure by 8 weeks post- MI. In contrast, impaired cardiac function 
evident at 3 days post-MI either persisted or worsened over the same 8 week period for the 
placebo group. These results were further confirmed using sophisticated MRI and 
computed 
tomography 
(CT) 
to 
image 
and 
quantify 
myocardial 
infarcts 
and 
repair91,92,95,96,97,98,99,100,101,102,103. 
 
MSCs delivered during these acute myocardial infarction experiments were found to 
engraft within the MI, and differentiated to express myocyte proteins, including α-actinin, 

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phospholamban, tropomyosin, and troponin T. Furthermore, MSCs were found in vascular 
structures and expressed VEGF and von Willebrand Factor, which suggesting that they also 
differentiated into vascular endothelium and/or smooth muscle. There was also a 
noticeable lack of inflammatory response, supporting the observations that MSCs do not 
elicit immune rejection, despite the absence of immunosuppressive drug therapy. Over 
time, the number of MSCs persisting in the myocardium decreased. 
 
Other experiments using intravenously-delivered MSCs at the time of coronary reperfusion 
homed to the myocardium, whereas MSCs injected 2 weeks post-MI preferentially 
engrafted into the bone marrow. Interestingly, it was found that MSCs express both SDF-1 
and CXCR4, and serum levels of both of these are up-regulated immediately post-MI and 
remain elevated for at least 2 weeks with MSC intravenous MSC infusion104. 
 
Similarly, in a chronic ischemic cardiomyopathy model using Gottingen mini-swine, 
autologous bone marrow-derived MSCs produced reverse remodeling105. At 12 weeks post-
MI, autologous MSCs were delivered to the infarct. Over the next 12 weeks, animals that 
received intramyocardial injected MSCs showed a significant reduction in scar burden via 
cardiac MRI (21.8+3.9% versus placebo, p<0.05), which could be seen as quickly as 3 days. 
Furthermore, there was significant improvement in regional contractility, global LV 
function, ejection fraction, and myocardial blood flow. The MSC therapy led to reverse 
remodeling, and reduced the circumferential extent of the infarct scar, suggesting the MSC 
therapy promoted the highly effective repair of ischemic cardiomyopathy. At a cellular 
level, it was found that the MSCs stimulated cardiac recovery by engrafting, promoted new 
blood vessels formation that increased tissue perfusion in the hypoperfused areas, formed 
new cardiac myocytes, and interacted with endogenous precursor cells to induce new 
cardiac myocyte formation. 
 
Further experiments clearly demonstrated that allogenic MSCs restore cardiac function in 
chronic ischemic cardiomyopathy by trilineage differentiation106. This was clearly 
demonstrated by transplantation of MSCs from male swine donors into female recipients. 
Immunohistological analyses against the Y-chromosome revealed that the allogenic MSCs 
differentiated into cells containing markers of cardiac, endothelial, and vascular lineages. 
MSCs were shown to engraft in infarct and border zones, and expressed α-sarcomeric actin, 
GATA-4, and Nkx2.5, indicating differentiation into cardiomyocytes. Very importantly, 
there was a direct correlation with the number of engrafting MSCs and the improvement in 
cardiac function. These studies also demonstrate the effectiveness of MSCs to treat chronic 
damage. 
 
These results provide strong rationale for the continued development of MSC-based 
cellular therapy and support ongoing human studies. Based on these pre-clinical studies, 
the FDA issued two INDs for clinical trials in patients with ischemic cardiomyopathy, and a 
third for non-ischemic cardiomyopathy.  
 
1.4.3 MSCs in Graft-Versus-Host Disease (GVHD) 

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MSCs have been successfully used to prevent GVHD in mice107. The MSCs were required to 
express functional iNOS and INFα receptor to convey this immunosuppressive function, in 
which cytokine-induced activation of iNOS inhibited T cell proliferation. 
1.4.4 MSCs in Pulmonary Disorders 
MSCs have been shown to contribute to tissue regeneration after lung injury108,109. In mice 
with lipopolysaccharide-induced lung injury, bone-marrow derived progenitor cells home 
in on the sites of inflammation and differentiate into endothelial and epithelial cells110. 
Similarly, MSCs are involved in rodent lung repair after elastase-induced pulmonary 
emphysema111, pulmonary hypertension produced by monocrotaline112, asbestos-induced 
pulmonary fibrosis113, and bacterial endotoxin-induced lung damage114. These and other 
studies have shown that MSCs contributed to pulmonary repair and regeneration by 
homing to sites of lung injury115,116,117. In particular, such homing has been elegantly shown 
using male murine MSCs infused into female recipients: through fluorescence in situ 
hybridization (FISH) against the Y-chromosome, MSCs were show to accumulate to sites of 
bleomycin-induced lung injury66,118. These allogenic MSCs appear to undergo mesenchymal 
to endothelial cell transition, or possibly to fuse with resident epithelial cells, since the 
FISH-labeled cells have an epithelial-like morphology. Likewise, allogenic human MSCs are 
effective at restoring normal fluid balance after endotoxin-induced acute lung injury in an 
ex vivo perfused human lung model [114], which may in part be due to release of MSC 
microvesicles [115, 116]. 
 
The allogenic and xenogeneic safety and efficacy of human MSCs has also been 
demonstrated in numerous animal models. For example, human MSCs are able to 
incorporate into murine lung epithelium [117], and are effective in repairing lung damage 
after endotoxin-induced acute lung injury in mice [118]. Furthermore, in the murine 
ovalbumin asthma model, infusion of xenogeneic human MSCs effectively decreased 
chronic airway inflammation, presumably due to their anti- inflammatory properties70. 
 
In addition, in-situ hybridization studies with co-staining for green fluorescent protein 
(GFP) and epithelial markers shows that GFP-labeled MSCs assume an epithelial phenotype 
at sites of lung injury and contribute to tissue repair [106, 119]. It is worth noting, 
however, that not all authors agree, with some suggesting that technical difficulties 
associated with immunofluorescence microscopy have led to the false conclusion that MSCs 
contribute to alveolar epithelium [120, 121]. 
 
1.5 
BMMSC previous Experience in Humans 
 
The use of allogeneic cellular products typically requires matching of the graft HLA to the 
donor in order to avoid graft rejection and graft versus host disease.  However, because 
MSCs do not express HLA, they represent a unique immunoprivileged cell population which 
can be used for allogeneic cellular therapy.  In addition, MSCs fail to induce proliferation of 
allogeneic lymphocytes in vitro and suppress proliferation of T cells activated by allogeneic 
cells or mitogens.  MSCs have also been shown to exert anti-proliferative, 
immunomodulatory and anti-inflammatory effects.  Many subjects have received allogeneic 

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MSCs and infusions have all been well tolerated. MSCs are currently being used at various 
stages in numerous clinical trials, including treatment of myocardial infarction, diabetes, 
graft-versus-host disease, osteogenesis imperfecta, Crohn’s disease, multiple sclerosis, 
spinal cord injury, stroke, and traumatic brain injury [50, 57, 80, 124-138]. 
 
1.5.1 Safety Information 
 
Allogenic MSCs have safely been used in a number of clinical trials, in complete accord with 
the high safety profile repeatedly observed in animal models [139]. This stems from the 
immunological status of MSCs: while allogenic grafts typically require HLA matching of 
donor to host to prevent tissue rejection, MSCs do not detectably express HLA, conferring a 
unique immune privileged status to these cells34,57,61.  Furthermore, MSCs exert anti-
inflammatory and immunomodulatory effects. They also do not induce proliferation of 
allogeneic lymphocytes, and suppress T-cell proliferation activated by allogeneic cells or 
mitogens. Together, these properties make MSCs uniquely suitable for allogenic therapy, 
and have repeatedly been shown to be well tolerated in patients. 
 
1.5.1.1 
MSCs Safety in Cardiac Disease  
 
The safety of allogenic MSCs has repeatedly been shown in clinical investigations of cellular 
cardiomyoplasty [40, 101, 135]. These studies revealed that allogeneic MSCs did not 
stimulate significant donor-specific alloimmune reactions [135]. The Poseidon trial 
(NCT01087996) showed that MSCs are immunoprivileged and immunosuppressive, and 
did not lead to acute immunogenic reactions [129]. No subject had symptoms indicative of 
reaction to the infused cellular therapy, and only 1 of the 15 patients had mounted any 
detectible donor specific alloreaction, which was of low antibody titer [135]. Of particular 
interest in these trials was that cellular therapy using allogenic MSC appeared more 
effective and safer than using autologous MSCs. It has been hypothesized that autologous 
MSC function could be impaired due to advanced age or patient co-morbidity, which 
allogenic MSCs would not be subject to [140, 141]. In a follow-up Phase II study using 53 
patients, no HLA-matching was performed, and MSC therapy was found to be safe and well-
tolerated at any of the 3 administered doses [76]. No deaths were reported, and no SAEs 
were attributed to the therapy; in fact, the number of AEs decreased in the therapeutic 
group compared to placebo. 
 
In the POSEIDON trial [80, 135], both allogeneic and autologous MSCs were associated with 
low rates of treatment-emergent serious adverse events (TE-SAEs), and no patients 
reported symptoms or indications of adverse reaction. The results showed that MSCs are 
immunoprivileged, immunosuppressive, and do not lead to acute immunogenic reactions. 
In an open-label pilot of the TRIDENT study (NCT02013674) to treat chronic ischemic left 
ventricular dysfunction secondary to myocardial infarction, subjects were infused with 
either allogenic or autologous MSCs [139]. SAEs were lower among the allogenic MSC-
treatment group that the autologous MSCs treatment group. 
 

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The Transendocardial Autologous Cells in Ischemic Heart Failure Trial (TAC-HFT) is an 8 
patients open-label phase 1 trial to assess the safety and preliminary efficacy of MSCs and 
bone marrow mononuclear cells (MNCs) in patients with ischemic cardiomyopathy. All 
patients tolerated the treatment well, and no adverse events were observed. 
 
1.5.1.2 
MSCs Safety in Graft Versus Host Disease (GVHD) 
 
As such, allogenic MSCs have been shown to be both safe and highly effective at treating 
steroid- resistant acute host-versus-graft disease (GVHD)35.  In this study, 55 patients were 
given 1 – 5 infusions of either HLA-matched or mismatched MSCs. The amount of cells 
delivered ranged from 0.4 – 9 × 106 MSCs/kg body mass. There was no association between 
the HLA matching and improvement, and no adverse events were observed or infusion-
related side-effects. 
 
1.5.1.3 
MSCs Safety in Pulmonary Disorders 
 
The therapeutic use of allogenic MSCs have also been examined for treating COPD [142, 
143]. No acute immunological reactions, infusional toxicities, deaths, or AEs related to the 
infusions were observed. In fact, a decrease in the inflammatory marker, CRP, was 
observed, suggesting that allogenic MSCs may generally decrease inflammation, 
particularly in older patients with co- morbidity. 
1.6 
Efficacy Information 
 
Efficacy of allogenic MSCs have been shown in numerous clinical trials. 
1.6.1 MSCs Efficacy in Cardiac Disease 
Numerous studies have shown the efficacy of MSCs to treat cardiac disease. 
Under the sponsorship of Osiris Therapeutics, an initial phase I study involving 10 centers 
and 53 patients demonstrated the provisional efficacy of allogeneic MSC therapy in patients 
with acute infarction39. Subsequently, a pilot study involving 8 patients with ischemic 
cardiomyopathy suggested that MSC therapy promotes the highly effective repair of 
ischemic cardiac damage [126]. The therapy produced reverse remodeling, and also 
reduced the circumferential extent of the infarct scar. 
There is also substantial clinical evidence that intravenous delivery of bone marrow-
derived mononuclear cells (MNCs) and MSCs can improve chronic left ventricular 
dysfunction. Under the sponsorship of Osiris Therapeutics, a multicenter phase I study 
suggested efficacy of intravenous allogeneic MSC therapy in patients who treated 3-10 days 
post-MI [144].  
Additionally, a phase I randomized trial provided preliminary evidence for the potential 
efficacy of allogeneic versus autologous MSCs delivered via transendocardial stem cell 
injection (TESI) in patients with chronic ischemic cardiomyopathy [145] 

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In the POSEIDON trial [80, 135], therapeutic MSC favorably affected patient functional 
capacity, quality of life, and ventricular remodeling. In this phase 1 open-label trial, 30 
patients were divided into 6 subgroups and given either autologous or allogenic MSC at a 
single dose or 20, 100, and 200 x 106 MSCs. Relative to baseline, autologous but not 
allogeneic MSC therapy was associated with an improvement in the 6-min walk test 
(6MWT) and the MLHFQ score. However, allogeneic MSCs reduced end-diastolic volume 
(EDV), possibly better than autologous MSCs. Both allogenic and autologous MSCs 
significantly reduced sphericity index and infarct size, but did not increase ejection fraction 
(EF). 
In the Transendocardial Autologous Cells in Ischemic Heart Failure Trial (TAC-HFT) open-
label phase 1 trial, 8 patients with ischemic cardiomyopathy were administered MSCs and 
bone marrow mononuclear cells (MNCs) [134]. The patients fell into one of two age groups: 
younger than 60 years old, or 60 years or older. These preliminary studies showed that 
MSC therapy improved 6MWT and MLHFQ scores, and produced reverse remodeling with 
~12% EDV reduction and regional function as measured by –Ecc, a cardiac MRI derived 
index reduced myocardial infarction size. Furthermore, older patients did not have an 
impaired response to MSC therapy compared to the young patients. 
A multi-center, randomized, double-blind, placebo-controlled study was performed to 
evaluate the safety and preliminary efficacy of allogeneic MSCs administered after 
myocardial infarction40. In this study, 53 patients were treated with one of three cell-dose 
levels of allogeneic MSCs (0.5, 1.6 and 5.0 cells/kg body weight) or placebo administered 
intravenously. No HLA matching was performed in this study and administration was 
found to be safe and well tolerated at all dose levels (with 5.3 adverse events per patient in 
the MSC-treated group vs. 7.0 in the placebo group). No deaths were reported and no 
serious adverse events were attributed to MSC administration. Compared to those who 
received placebo, patients that received MSCs had improvement in the frequency of 
arrhythmic events and premature ventricular contractions, post-event ejection fraction for 
patients with major anterior wall infarctions, overall clinical status, and notably post- 
infusion pulmonary function as measured by FEV1 percent predicted (increased 17% in 
the MSC- treated group vs. 6% for placebo group, p < 0.05). 
Cumulatively, these data support the hypothesis that cellular cardiomyoplasty using 
allogeneic MSC therapy is a safe and effective. These results formed the basis for the 
approved CRATUS study on aging frailty (NCT02065245). 
1.6.2 MSCs Efficacy in Graft Versus Host Disease (GVHD) 
In a phase II trial for treating acute GVHD, 55 patients received between 1 or more 
intravenous infusions of 1.4 x 106 allogenic MSCs/kg body mass (median dose)35.  Twenty-
seven (27) patients received one dose, 22 received two doses, and 6 received 3-5 doses. 
The MSCs were obtained from HLA-identical sibling donors (n=5), haploidentical donors 
(n=18), or HLA-mismatched donors (n=69). Thirty (30) of the patients had a complete 
response, and improvement was seen in a further 9 patients. The complete responders had 
significantly higher 1-year and 2-year survival rate. Furthermore, the response rates were 
not associated with HLA-matching. 

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1.6.3 MSCs Efficacy in Pulmonary Disorders 
The therapeutic use of allogenic MSCs have also been examined for treating COPD [143, 
146]. Patients received 4 monthly infusions of 1 x 108 MSCs. While the preclinical results 
indicated the promise of MSCs to treat COPD, preliminary efficacy results suggest that, 
while not detrimental to the patients, MSCs may not be effective at treating this condition. 
However, the sample size for these preliminary trials was small, so further investigation is 
required. 
1.6.4 MSCs Efficacy in Endothelial Disorders and Metabolic Syndrome 
Mesenchymal stem cells (MSCs) have the potential for clinical benefit in the metabolic 
syndrome by virtue of their anti-inflammatory, antifibrotic, and pro-angiogenic 
properties54,55, and their ability to stimulate endogenous progenitor cells [57, 147]. Thus, it 
was recently examined whether MSCs are capable of stimulating the bioactivity of 
circulating EPCs and improve endothelial function in failing circulation77. The results 
showed that allogeneic, but not autologous, MSCs improve EPC bioactivity and endothelial 
function in heart failure patients, regardless of the etiology. These findings suggest a novel 
clinical beneficial effect of allogeneic MSCs transplantation as a potential general treatment 
for disorders associated with endothelial dysfunction. 
1.6.5 Tabulated Previous Human Experience 
Table 2.  Previous Human Experience 
Trial Name 
Start 
Date 
PI 
Disease N 
Cell 
Doses 
Safety 
Result
Efficacy Results 
Stem Cell Therapy 
for Vasculogenesis 
in Patients With 
Severe Myocardial 
Ischemia 
2005- 
Dec 
Kastrup, J 
CAD 
31 3 - 72 
Safe 
3M and 6M post 
↑ Exercise 
↓ Angina attacks 
↑ Cardiac function 
3 years post 
↑ Exercise 
↓ Angina Rates 
Combined 
CABG and 
Stem- 
2006- 
Oct 
Harjula, 
A 
Patila, 
CAD 
39 5.2 - 13.5 
Safe 
↓Local scar 
No Δ LVEF 
Cell Transplantation 
for Heart Failure 
TAC-HFT 
2008- 
Aug 
Heldman, 
A 
CAD 
59 100,  200 
placebo 
Safe 
↑ MLHFQ 
↑ 6 minute walk test 
↓ Infarct size 

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Poseidon 
2010- 
Mar 
Hare, J 
CAD 
30 20, 100, 
200 
Safe 
↓ Mean EED 
↓ SI 
Autologous MSCs 
↑ 6 minute walk test 
↑MLHFQ, 
Allogeneic MSCs 
↓ LVED 
OPTIPEC 
2005- 
Jan 
Emmerich, J PAD/ 
CLI 
20 
Safe 
Active 
neoangiogenesis 
Study on Induced 
Wound Healing 
Through 
Application of 
Expanded 
Autologous Bone 
Marrow Stem 
Cells in Diabetic 
Patients With 
Ischemia-induced 
Chronic Tissue 
Ulcers Affecting the 
Lower Limbs 
2005- 
Aug 
Tschoepe, D PAD/ 
CLI 
22 ~50 
Safe 
↑Microcirculation 
A Phase I Study of 
Human Cord Blood- 
Derived 
Mesenchymal Stem 
Cell Therapy in 
Patients with 
Peripheral Arterial 
Occlusive Disease 
2007- 
May 
Kim, D 
PAD/ 
CLI 
8 10 
Safe 
NoΔ ABI 
↑ Mean value pain- 
free walking distance 
Complete ulceration 
healing in 3 patients 
No amputations, 
↑Angiography scores 
Phase II 
Combination Stem 
Cell Therapy for the 
Treatment of Severe 
Coronary Ischemia 
(CI) 
2008- 
Nov 
Lasala, G 
PAD/ 
CLI 
26 9 
Safe 
↑Walking time ↑ABI 
↑Perfusion via 
99mTc-TF 

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1.7 
Safety and Efficacy of Multiple Doses of MSCs 
Active clinical trials and ongoing preclinical work have increasingly demonstrated the 
therapeutic efficacy and safety of allogeneic mesenchymal stem cells (MSCs). Mesenchymal 
stem cells are both immunoprivileged and immunosuppressive, thereby enabling their 
allogenic allograftic use [148]. For example, the POSEIDON study addressed the major issue 
of the use of allogeneic MSCs as a cell-based therapeutic [135]. 
Accumulating preclinical evidence now also supports the concept that repeated doses 
and/or co- administration of MSCs could further enhance the therapeutic outcomes. This is 
an extremely important area for research, since repeat dosing could potentially have an 
additive effect and/or reverse disease pathology, depending on the disorder. 
Several clinical studies have demonstrated that multiple injections of MSCs are well 
tolerated with minimal side-effects; are safe; and exhibit no detriment to efficacy over 
single doses.   For example, results from Franco Locatelli’s group clearly demonstrate the 
safety and efficacy of multiple MSC infusions in children with steroid-refractory acute graft 
versus host disease (aGvHD) [127]. Doses in these studies were 1-2x106 MSCs/kg recipient 
body mass, and each child received on average 2 doses (range was 1-13 doses) separated 
A Randomized, 
Double Blind, 
Multicentric, 
Placebo Controlled, 
Single Dose, Phase - 
i/ii Study Assessing 
the Safety and 
Efficacy of 
Intramuscular ex 
Vivo Cultured Adult 
Allogeneic 
Mesenchymal Stem 
Cells in Patients 
With Critical Limb 
Ischemia (Cli) 
2009- 
Apr 
Suresh
, K S 
PAD/ 
CLI 
20 2/kg or 
placebo 
Safe 
↑ABPI 
↑TcPO2 
Mesenchymal Stem 
Cells in Multiple 
Sclerosis (MSCIMS) 
2008- 
Oct 
Connick 
MS 
18 Autologous 
1-2/kg 
Safe 
No efficacy data 
AllogeneiC Human 
Mesenchymal Stem 
Cells (hMSC) in 
Patients With Aging 
FRAilTy Via 
IntravenoUS 
Delivery. (CRATUS) 
2014- 
Feb 
Hare, J 
Frailty 
45 Allogeneic 
20, 100 or 
200 MSCs 
per 
infusion 
Safe 
↑MMSE scores 
↓Inflammatory 
markers 

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on average by 15 dy (range 3- 43 dy). Their results indicated increased effectiveness when 
the therapy was commenced early in the disease. Furthermore, their results indicated the 
therapeutic benefits of repeat doses to patients who did not achieve complete remission 
after a single dose. 
In another very interesting study, a single patient with aggressive relapsing-remitting 
multiple sclerosis received MSC infusions for 4 years, starting after the second year of 
disease onset [128]. Eight sets of injections were given every 3-9 months apart, using either 
autologous bone marrow-derived MSCs, or allogenic umbilical-derived MSCs, ranging from 
1.3 x107 - 3.27 x 108 cells per intravenous injection. Throughout the treatment period, the 
patient showed no disease progression clinically or radiologically. And in fact, the patient 
showed significant improvement (EDSS score improved from 3.5 to 2.0), oligoclonal bands 
were no longer detected, and many lesions that were observed prior to commencement of 
the therapy had resolved. All of which occurred without significant adverse effects. 
In another study by Kurtz’s group, compassionate use of adipose-derived MSCs were used 
to successfully treat a variety of autoimmune diseases in which other treatment options 
had been exhausted [149]. These included autoimmune inner ear disorder, multiple 
sclerosis, polymyositis, atopic dermatitis, and rheumatoid arthritis.  The patients received 
1-6 intravenous infusions of 2 x 108 MSCs within 1 month, and showed considerable 
improvement over the following months. Although the sample size was small, precluding 
statistical analyses, the preliminary results warrant further studies. In short, their results 
demonstrated the safety of MSCs, and suggest a therapeutic advantage to multiple MSC 
injections. 
A Phase II study on the 3-year efficacy of allogenic MSCs in the treatment of system lupus 
erythrematosus (SLE) was reported by Lingyun Sun’s group [150]. Their results 
demonstrated/confirmed the therapeutic efficacy of MSCs in treating SLE. However, no 
advantage was found by administering a second or higher dose of MSCs. Despite this lack of 
additional efficacy over a single dose, the results of this study confirmed the safety of 
multiple infusions of MSCs. It is also worth noting that the doses (1x106 MSCs/kg body 
mass) were administered only 1 week apart, and a potential benefit of a longer therapeutic 
dosing interval, e.g., monthly, has yet to be assessed. Along these lines, a recent report on 
the use of MSCs to treat chronic obstructive pulmonary disease (COPD) showed minimal 
therapeutic efficacy after 2 years [142]. While these preliminary results were somewhat 
disappointing, they nevertheless again demonstrated the safety of repeated MSC infusions, 
which were given 4 times at 30-day intervals (1x108 MSCs/infusion). 
Taken together, these various clinical studies provide a solid rationale for repeat MSC 
infusions. In no case did the administration of multiple doses lead to a significant increase 
in the frequency of adverse effects, or to a decrease in therapeutic efficacy over a single 
dose. In many cases, repeated infusions indeed improved clinical outcomes, demonstrating 
an additive effect of MSC therapy.  Given these promising results, investigations are now 
warranted to determine optimal dosing frequency and total doses of MSCs to administer. 
1.8 
Pharmacology and Toxicology Studies of BMSC 
 

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Preclinical data suggest that MSCs may safely be used in the treatment patients with 
chronic inflammation to produce cytokine suppression. Using the murine bleomycin model, 
several groups have shown that the administration of stem cells ameliorates bleomycin 
induced lung injury with no significant adverse effects.   
 
Lee et al intravenously administered 1x106 bone marrow derived MSCs to rats treated with 
bleomycin and found a decrease in bleomycin induced lung edema, neutrophil infiltration, 
collagen deposition, and overall mortality with no adverse effects reported93.  Similarly, 
Ortiz et al intravenously administered 5 x 105 bone marrow derived MSCs to mice with no 
adverse effects reported.  They found that after bleomycin exposure, MSCs home to sites of 
lung injury, lead to decreased fibrosis and extracellular matrix collagen deposition, and 
contribute to tissue repair89.  Rojas et al intravenously administered 5 x 105 allogeneic 
bone marrow derived MSCs to mice treated with bleomycin and observed that lung injury 
attracts bone marrow derived MSCs via the production of soluble factors like G-CSF and 
GM-CSF which lead to MSC proliferation and migration and ultimately improved survival 
with no reported adverse effects94.   
These findings appear to extend beyond bone marrow derived MSCs.  Cargnoni et al 
administered fetal membrane derived cells (both allogeneic murine and xenogeneic 
human) to bleomycin treated mice and found that placental derived stem cells, like MSCs, 
localize to the lung and reduce tissue damage associated with bleomycin exposure 
regardless of source or route of administration (intravenous, intraperitoneal, or 
intratracheal)88.   They did find that intraperitoneal and intratracheal administration of 
cells led to mild to moderate lung inflammation but no fibrosis in the absence of bleomycin 
injury.  Importantly, this was not seen with intravenous administration of cells.  In another 
murine model, xenogeneic human umbilical cord derived MSCs were also shown to home 
to sites of bleomycin induced lung injury, inhibit the production of pro-inflammatory 
cytokines, and reduce lung injury and collagen deposition with no adverse effects 
reported90. 
Table 3. Results of preclinical animal studies of mesenchymal stem cell therapy for IPF. 
Study 
Model 
Cell Type 
Cell Delivery 
and Dose 
Safety Results 
Efficacy Results 
Lee at al, 
2006 
Rat 
Allogeneic 
BMMSCs 
Intravenous, 
1 x 106 cells 
No adverse 
effects 
reported. 
Reduced edema, 
neutrophil 
infiltratration, 
collagen deposition. 
Improved survival. 
Ortiz et 
al, 2003 
Mouse 
Allogeneic 
BMMSCs 
Intravenous, 
5 x 105 cells 
No adverse 
effects 
reported. 
Reduced 
inflammation and 
collagen deposition. 
Rojas et 
Mouse 
Allogeneic 
Intravenous, 
No adverse 
effects 
Reduced pro-
inflammatory 

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al, 2005 
BMMSCs 
5 x 105 cells 
reported. 
cytokines. 
Improved survival. 
Cargnon
i et al, 
2009 
Mouse 
Fetal 
membrane 
derived 
(Allogeneic 
murine and 
xenogeneic 
human) 
Intra-
peritoneal,  
4 x 106 cells 
 
Intratracheal
, 1 x 106 cells 
Intravenous, 
1 x 106 cells 
 
Mild to 
moderate lung 
inflammation 
but no fibrosis 
induced by 
intraperitoneal 
or intratracheal 
administration. 
No adverse 
effects reported 
with I.V. 
administration. 
Decreased 
neutrophil 
infiltration and 
fibrosis regardless 
of route of 
administration or 
source of cells. 
Moodley 
et al, 
2009 
Mouse 
Xenogeneic 
human 
umbilical 
cord 
derived 
MSCs 
Intravenous, 
1 x 106 cells 
No adverse 
effects 
reported. 
Reduced 
inflammation, pro-
inflammatory 
cytokine 
production, and 
collagen deposition. 
 
In addition to safety data from preclinical animal studies, many patients have received 
allogeneic MSCs in clinical trials and infusions have all been well tolerated.  
 
A multi-center, randomized, double-blind, placebo-controlled study was performed to 
evaluate the safety and preliminary efficacy of allogeneic MSCs administered after 
myocardial infarction76.  In this study, 53 subjects were treated with one of three cell-dose 
levels of allogeneic MSCs (0.5, 1.6 and 5.0 cells/kg body weight) or placebo administered 
intravenously.  No HLA matching was performed in this study and administration was 
found to be safe and well tolerated at all dose levels (with 5.3 adverse events per subject in 
the MSC-treated group vs. 7.0 in the placebo group).  No deaths were reported and no 
serious adverse events were attributed to MSC administration.  Improvements were seen 
in subjects receiving MSCs as compared with those receiving placebo in the frequency of 
arrhythmic events and premature ventricular contractions, post-event ejection fraction for 
subjects with major anterior wall infarctions, overall clinical status, and notably post-
infusion pulmonary function as measured by FEV1 percent predicted (increased 17% in 
the MSC-treated group vs. 6% for placebo group, p < 0.05).   
 
Allogeneic MSC infusion has also been studied in a phase II trial of MSCs for the treatment 
of severe acute graft versus host disease68.  In this study, 55 subjects received 1-5 
intravenous infusions of 1.4 x 106 cells/kg body weight from HLA matched and mismatched 
donors.  A complete response was seen in 30 subjects and improvement was seen in 9 

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patients.  Of note, response rates were not associated with HLA-matching.  No infusion 
related side effects were noted and no long term adverse events were observed.       
 
The safety and efficacy of allogeneic MSCs for the treatment of refractory lupus has also 
been explored119.  Fifteen subjects received a single intravenous infusion of 1 x 106 cells/kg 
body weight.  MSCs were derived from family members but were not HLA-matched.  At 12 
months, all subjects had improvement in disease activity as measured by 24-hour 
proteinuria (decreased from 2505.0±1323.9 to 858.0±800.7 mg/24hr, p<0.05) and SLE 
Disease Activity Index scores (decreased from 12.2±3.3 to 3.2±2.8, p<0.05).  No serious 
adverse events were noted in any of the subjects. 
 
1.9 
UCMSCs 
The alternative sources of MSC is of significant value. It has been reported that MSC could 
be isolated from various tissues, including periosteum, trabecular bone, adipose tissue, 
synovium, skeletal muscle, deciduous teeth, fetal pancreas, lung, liver, amniotic fluid, cord 
blood and umbilical cord tissues98,120,121. Among those, cord blood and UC may be ideal 
sources due to their accessibility, painless procedures to donors, promising sources for 
autologous cell therapy and lower risk of viral contamination. However, the data on the 
isolation of cord blood-derived MSC are controversial120,122. In addition, the process of 
isolation of MSC is at the expense of losing hematopoietic stem cells in cord blood. Thus, UC 
should be focused on as an alternative source of MSC. 
MSC’s can be isolated from many different tissues like, bone marrow, adipose tissue, dental 
pulp etc. Umbilical cords are readily accessible, fewer limitation, (a usual medical waste) 
and are more similar to early embryonic sketch of human cell biology. Cells in the Umbilical 
cord are divided into different groups based on the regions like, Wharton’s Jelly, Cord 
lining, and perivascular area, or cell type, epithelial, stromal, and smooth muscles; 
respectively, of umbilical cord. However, majority of research and investigation on 
Umbilical cord in vivo are based on use of accumulated fraction of whole umbilical cord 
tissue or Wharton’s Jelly/perivascular area. MSC’s derived from Wharton’s Jelly matrix, 
located close to the vasculature of cord tissue, are more primitive, proliferative and 
immunosuppressive than their counterparts. MSC cultured from individual cord digested 
enzymatically, demonstrated plastic adherence, flow cytometric profile and immune-
profile showed no significant difference than its adult counterpart.  
The healing potential of UC derived stem cells and other MSC’s in regenerative medicine 
serves as direct repairing, tissue remodeling, paracrine effects and influence on 
microenvironment and immunomodulation. Researchers have reported that gradual 
exposure to MSCs at a lesion site resulted in accumulation of various therapeutic proteins 
that were secreted and reacted with the microenvironment. Therefore, many different 
proteins secreted by MSCs influenced paracrine actions for recovery of the lesion site. The 
therapeutic proteins secreted by MSCs include growth factors, cytokines, extracellular 
matrix proteins, and antioxidants. When the paracrine effect of MSCs was assessed in 
various disease models, there were similar therapeutic effects through the actions of the 
proteins mentioned above. Although the general characteristics of MSCs include stemness, 

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tropism, differentiation, motivation, and a therapeutic paracrine effect, it is possible that 
the origin of the donor cells may influence their therapeutic effects. 
UCMSCs shared most of the characteristics with BMMSCs, including fibroblastic 
morphology, typical immunophenotypic markers, cell cycle status, adipogeneic and 
osteogenic differentiation capacity, cytokine spectrum as well as hematopoiesis-supportive 
function. However, several differences have been observed. 
The CFU-F frequency was significantly higher in UC-derived nucleated cells than in BM-
derived nucleated cells. Secondly, the proliferation analysis revealed that UCMSC have a 
faster population doubling time123.  
With regard to their multipotency124,125,126,127 UCMSC can be differentiated into bone, 
cartilage, neural and muscle cells as well as cardiomyocyte-like cells, as they express 
cardiac troponin-I and N-cadherin108,124,125,126,127,128. 
Our group and other groups, successfully managed to grow UCMSC under GMP-compliant 
culture conditions, while retaining their phenotypic and functional properties112.. 
The Superiority of UCMSCs in Clinical Application 
BM is considered as a traditional source of MSCs, and most of the knowledge concerning 
MSCs comes from BM studies. However, several limitations restrict the clinical application 
of BMMSCs. Harvesting BMMSCs involves an invasive and painful procedure, which can 
cause infection, bleeding, and chronic pain. On the contrary, UCMSCs are obtained after 
delivery of a baby from a sample that would be discarded inevitably. The process is 
noninvasive, painless, and harmless for the mother and the baby. UC contains a significant 
amount of MSCs which can be easily collected and cultured98,113. In vitro, UCMSCs have 
greater expansion capability and faster growth rate98,123,129,130, indicating the advantage for 
rapid expansion and consequent downstream application. UCMSCs express a lower level of 
HLA-class I than BMMSCs98. UCMSCs appear to have greater immunosuppressive effects130, 
indicating their better role in the management of GVHD. Therefore, UC represents a good 
alternative source of MSCs and should not be discarded as medical waste131. 
1.10 UCMSCs: Preclinical Experience 
 
The use of adult Bone Marrow is considered an extensive and renowned source of MSCs. 
MSCs can also be obtained from umbilical cord, which was contemplated as clinical waste 
(Zhimai et al, 2012).  
 
In a study for the treatment of Spinal cord injuries in dogs (Hak-Hyun et al, 2012), the study 
concentrated on the assimilation and survival of allogeneic MSCs (Adipose derived MSC, 
Bone Marrow MSC, Umbilical Cord Blood MSC, and Wharton’s WJ derived MSC) in the 
injured spinal cord. Overall, 6.0 × 106 cells were injected into the parts of the injured spinal 
cord. The results showed macrophage infiltration into the lesion epicenter in the MSCs 
group and reduced levels reactive astrogliosis but most notably there was a decrease of 

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COX-2 protein in Umbilical Cord stem cell compared to the other MSC groups (Hak-Hyun et 
al, 2012). The Levels of GFAP were decreased, while the expression of Tuj1, NeuN, and 
NF160 were increased compared to the other MSCs groups. As a result, there was less 
inflammation to the site and more nerve regeneration, as well as neuroprotection (Hak-
Hyun et al, 2012). This study concluded that allogeneic MSCs can survive in injured spinal 
cords where they can develop into host tissue without the need of immunosuppressive 
agents and improve hind-limb function (Hak-Hyun et al, 2012). 
 
Another study (Mei-Juan et al, 2011) researched the effects of UC MSCs on ataxic mice by 
cytosine beta-D- arabinofuranoside (Ara-C). 2×106 HU-MSCs were delivered intravenously 
once a week for three consecutive weeks. The use of open field test and rotarod test, 
measured the Neurological function score of the mice on a weekly basis. The results 
showed that ataxic mice (n = 6) remained on the machine much shorter than normal ICR- 
mice (n = 6) (68.11 ± 9.59 s vs. 330.11 ± 51.87 s, p < 0.01). On week 7 there was an 
improvement in behavior performance in terms of relief of behavior impairment and 
morphologic atrophy of ataxic mice. By the 9th week a significant improvement was 
achieved following UC-MSCs treatment (UC-MSCs vs. control: 90.56 ± 13.75 seconds vs. 
58.00 ± 9.43 s, p < 0.05) until the 12th week (Mei-Juan et al, 2011). With the Open field test, 
there was also a difference between the control group (n = 6) and UC-MSCs group (n = 6) at 
week 6 post-transplant and a statistical significance at the 8th week (74.33 ± 10.05 vs. 
128.67 ± 16.98, p < 0.05) (Mei-Juan et al, 2011). These results indicated 8 weeks after the 
application UC-MSCs implantation considerably improved the motor skills of ataxic mice. 
Cerebellar atrophy was also relieved as well as a decrease in the number of apoptotic cells 
in the therapeutic group using UC-MSCs (Mei-Juan et al, 2011). Vascular endothelial growth 
factor (VEGF) and insulin-like growth factor-1 (IGF-1) had a heighted expression in UC-
MSC treated mice. 
 
 
Table 4:  
Study 
Model 
Cell Type 
Cell Delivery and 
Dose 
Safety 
Results 
Efficacy Results 
Mei-Juan 
et al, 
2011 
Rat 
Allogeneic 
Intravenous 
No 
adverse 
effects 
reporte
d. 
Relief of behavior 
impairment and 
morphologic 
atrophy  
UCMSCs 
2×106 HU-MSCs  

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Hak-
Hyun et 
al, 2012 
Dog 
Allogeneic 
Cranial, 
epicenter, and 
caudal lesions of 
the spinal cord 
parenchyma; 20 
μl/site  
No 
adverse 
effects 
reporte
d. 
Improve hind- 
limb function  
UCMSCs 
6.0 × 106 cells  
UCMSCs 
106 MSC/200 
μL/PBS 
UCMSCs 
6 × 105 hUC-MSCs 
UCMSCs 
5 × 105 hUC-MSCs 
 
1.11 UCMSCs: Previous Experience in Humans 
 
Due to its noninvasive procedure and its lesser possibility for genetic alterations, Human 
UC tissue is viewed as a greater MSC source for bone regeneration. It has also shown great 
therapeutic effects in many diseases in animal studies due to their ability for differentiation 
and self- renewal132. Native MSCs (CD90+, CD45-,  and CD235a- cells) and native ECs 
(CD31+ , CD235a-, and CD45-) from numerous experiments showed that from a single UC 
donation, the number of cells obtained was higher on an average than a 20-ml specimen of 
BM aspirate (average 90- and 11-fold, respectively)132. In this procedure, the UC cells were 
set apart from 19 cesarean section patients that were on their full term. About 0.2 g of UC 
tissue was mechanically cut up into miniature pieces. 7.5 × 10
7 nucleated cells/per gram of 
tissue was considered the average released UC isolates132. 
Sun et al, 2010118 did a study to understand the safety and efficacy of allogeneic UC MSCT in 
patients with severe and treatment-refractory systemic lupus Erythematosus (SLE). A 
single-arm trial was conducted using 16 SLE patients who either had life-threatening 
visceral involvement or whose disease wasn’t applicable to standard treatment. From 2007 
to 2009, the results concluded with a significant improvement in the Systemic Lupus 
Erythematosus Disease Activity Index (SLEDAI) score, anti-dsDNA antibody, renal function, 
levels of serum ANA, complement C3, and serum albumin. There was also a balance 
between TH1- and Th2 related cytokynes. This resulted in a reduction of disease activity in 
patients. For each patient who had lupus nephritis, there was a 24-hour proteinuria 
measurement that had impaired renal function at baseline. At the 3-month visit, 15 patients 
had a decreased effect in proteinuria. Eight patients had greater reduction in proteinuria 
after 6 months. Two patients stayed negative of preoteinuria after 2 years118. There was 
higher than normal elevated serum creatinine levels at baseline for six patients. This 
improved after 3 months and even greater at 6 months118. Two out of16 patients had 

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seizures and after the UC MSCT, none demonstrated recurrences. In some patients that had 
severe hypertension, there symptoms were controlled after the UC MSCT118. 
LU et al, 200698 created a study using 36 UC and six BM samples. Fibroblastic-like 
morphology, adipogenic and osteogenic differentiation potentials immunophenotype, 
hemotapoiesis supportive function and cell cycle status are some of the mostly shared 
characteristics that UC-MSC and BM-MSC share, yet there are still other differences that 
have set them apart. For example, CFU-F, which represent mesenchymal progenitor cell, 
frequency tested lower in BM nucleated cells compared to UC nucleated cells. Another 
comparison with UC- MSC, BM-MSC have higher levels of expression CD106 and HLA-ABC 
and a lower proliferation capacity (LU et al, 2006). In contrast, proliferation analysis has 
shown that UC-MSC as opposed to BM-MSC have a faster population doubling time and it 
maintained that way even after 30 passages, while BM-MSC decreased in population 
doubling time after P698. 
Table 5 
Study 
Model 
Cell Type 
Cell 
Delivery 
and Dose 
Safety Results 
Efficacy Results 
Kouroupis 
et al, 
2013132 
Human 
 
 
Allogeneic 
 
 UCMSCs 
7.5 × 107 
nucle-ated 
cells/per 
gram of 
tissue  
No adverse effects 
reported. 
Higher count of 
MSC and EC in a UC 
donation compared 
to 20 mL of BM 
aspirate 
 
Sun et al, 
2010118 
Human 
Allogeneic 1 × 106 per 
kg of body 
weight 
No adverse effects 
reported. 
Reduced 
proteinuria, 
decreased (SLE)  
UCMSCs 
Lu et al, 
200698 
Human 
Allogeneic 
1 ×106/cm 
mean 
number of 
nucleated 
cells  
No adverse effects 
reported. 
HigherCFU-F 
frequency, faster 
population 
doubling time 
UCMSCs 
Hu et al, 
2013 
Human Allogeneic Intravenous 
1.5 –
3.2×107 
No adverse effects 
reported. 
Reduced dosage of 
insulin 

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UCMSCs 
/WJMSCs 
cells 
supplementation  
Wang et 
al, 
2015128 
Human 
Allogeneic Central line, 
0.8-1.6 x 
106/kg cells 
No adverse effects 
reported. 
Decrease in 
hematuria  
UCMSCs / 
WJMSCs 
 
Hu et al, 2013 administered two doses of 1.5–3.2 × 107 of WJ-MSC to 15 patients in a 
double-blind study for an onset of type 1 diabetes. It was done at a 4-week interval by 
intravenous delivery. For 3 out of 15 the use of insulin supplementation was terminated 
and 3 out of 15 the daily dosage was decreased from 15-50%. 8 out of 15 patients, the 
dosage was decreased by more than 50%, all within a period of 24 months. There was just 
1 patient that did no effect from the MSC treatment (Hu et al, 2013). There were no adverse 
effects during the treatment. 
A study done by Wang et al, presented that HC (Late-Onset Hemorrhagic Cystitis) though a 
common complication after allogeneic hematopoietic stem cell transplantation, can be 
detrimental to the patient by causing hemorrhagic inflammation of the bladder. There is a 
continuous association with Graft-versus- host disease (GVHD) and late onset of HC. 1-3 
doses of 0.8–1.6 × 106 /kg of WJ-MSC were administered through a central line to seven 
patients that contained this disease. Due to this stem cell treatment, gross hematuria was 
relieved within 2-12 days as opposed to patients that did not have this treatment, which 
took longer to clear up, thus showing a significant difference between the two groups. 
Multiple results have confirmed that WJ-MSC are a helpful treatment for late onset 
hemorrhagic cystitis128. 
Table 6 
Study 
 
Phase 
Model 
Cell Type 
Cell Delivery 
and Dose 
Identifier 
Clinical Study of 
Umbilical Cord Tissue 
Mesenchymal Stem Cells 
(UC-MSC) for Treatment 
of Osteoarthritis 
Translational Biosciences 
Panama City, Panama 
 
Ruben Berrocal, MD 
 
 
 
I/II 
Human 
Allogeneic  
UC-MSCs 
 
Intra-
arterial  
Arm 1: will 
receive one intra-
articular injection 
of UC-MSC into 
the Knee and 
Arm 2: will 
receive IV UC-
MSC once per 
day for 3 
consecutive days. 
NCT02237846 

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An Open-label, Non-
randomized, Phase 
I/II Study of 
Allogeneic Human 
Umbilical Cord 
Tissue-Derived 
Mesenchymal Stem 
Cells (UC-MSC) and 
Liberation Therapy 
(When Associated 
With Chronic 
Cerebrovascular 
Venous Insufficiency) 
in Patients With 
Relapsing Remitting 
Multiple Sclerosis 
(RRMS) 
Novo Cellular 
Medicine Institute 
San Fernando, 
Trinidad, Trinidad 
and Tobago 
PI: Dr. Bill Brashier, 
M.D. 
 
 
 
I/II 
Human 
Allogeneic  
UC-MSCs 
IV-
infusion 
& 
Intrathecal 
 
Intravenous 
administration 
of 50 million 
Allogeneic UC-
MSCs and 
intrathecal 
administration 
of UC-MSCs in 
dose of 100 
million along 
with liberation 
therapy (when 
associated with 
CCSVI) 
NCT02587715 
Feasibility Study of 
Umbilical Cord Tissue 
Derived Mesenchymal 
Stem Cells (UC-MSC) 
in Disease Modifying 
Anti-Rheumatic Drugs 
(DMARD) Resistant 
Rheumatoid Arthritis 
Translational 
Biosciences 
Panama City, Panama 
PI: Jorge Paz-
Rodriguez, MD 
 
 
 
 
I/II 
Human 
Allogeneic  
UC-MSCs 
Not available  
NCT01985464 
 
1.12  Pharmacology and Toxicology Studies of Mesenchymal Stem Cells 
 

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Preclinical data suggest that UC MSCs may safely be used in the treatment of patients with 
chronic inflammation to produce cytokine suppression.  
 
New studies are developing for the future and prevention of health incidents. Radiation 
injuries can occur as a result of nuclear accidents and radio-therapy. One of the most 
radiosensitive intraabdominal organ is the small intestine. The function and integrity of the 
small intestine can be affected by abdominal irradiation, which can cause acute and/or 
chronic gastrointestinal tract (GIT) disorders (Zhimai et al, 2012).  After the injection of 
high molecular weight fraction (HMWF) from hypoxic-conditioned media of UC MSC on 
radiation-induced intestinal injury of 10 Gy (60Coγ-ray), there was an increased survival 
rate in mice, improved small intestinal structural integrity and a decrease of diarrhea 
occurrences (Zhimai et al, 2012). Zhimai concluded that the infusion of an MSC-secreted 
HMWF has a key role in accelerating the recovery of radiation-induced intestine structural 
damage and averting radiation-induced intestinal injury in an abdominal irradiation mice 
mode. Thus, presenting a therapeutic approach for treatment of radiation induced injury 
(Zhimai et al, 2012).  
 
(Koh 
et 
al, 
2008) 
implanted 
hUC-MSCs 
into 
the 
damaged 
hemisphere 
of 
immunosuppressed ischemic stroke rats. Results showed a reduction in infarct volume and 
an improvement of neurobehavioral function relative to control rats. Three weeks after 
implantation, a great amount of the hUC-MSCs that was implanted were existent in the 
damaged hemisphere, even some of these cells showed levels of neuron-specific markers. 
There was also an indication of increased Nestin expression in the hippocampus in the 
hUC-MSC-implanted group as appose to the control group. Signs of neuroprotection on 
neurological diseases (i.e Parkinson diseases) in animal were exhibited in transplanted HU-
MSCs133. The study concludes that hUC-MSCs like most MSCs could possibly have 
advantages for the induction of neuronal differentiation133.  
 
The loss of neurons and glia, degeneration of axons, and demyelination around the lesion 
site are common effects of mammalian spinal cord injury. Post lesion scar barriers and 
myelin- associated inhibitors can obstruct axonal regeneration. Even intrinsic cell renewal 
after application of mitogenic agents, does not have the capability to permit the recovery of 
a spinal cord injury (Chang-Ching et al, 2008). HUMSCs can differentiate into chondrogenic, 
adipogenic, myogenic, and myogenic osteogenic cells in vitro. In this study, using a 
complete transection model in rats, (Chang-Ching et al, 2008) assessed the effect of 
transplantation of UCMSCs on axon regeneration in the injured spinal cord. Within the first 
three weeks after transplantation, signs of recovery in locomotor function were detected 
and showed significant difference between the control group, which had no locomotor 
function throughout the 16-week trial, and the transplanted groups. By the end of the 
study, (Chang-Ching et al, 2008) uncovered that the transplanted rats were able to 
synchronize movement between the forelimbs and the hind-limbs to achieve a walking 
motion. This study shows proof that transplantation of HUC-MSCs can help with the 
locomotor recovery, depression in the activities of microglia and reactive astrocytes, 
reduction of astroglial scarring in the lesion, and restoration of corticospinal fibers after 
spinal cord transection in rat (Chang-Ching et al, 2008). 
 

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Table 7 
Study 
Model 
Cell Type 
Cell Delivery 
and Dose 
Safety 
Results 
Efficacy Results 
Zhimai 
et al, 
2012 
Mice 
Allogeneic Intravenously 
by the tail 
No 
adverse 
effects 
reported. 
Accelerates the 
recovery of 
radiation-
induced 
intestine 
structural 
damage 
UCMSCs 
10^6 
MSC/200 
μL/PBS 
Koh et 
al, 2008 
Rat 
Allogeneic 
Implanted 
into the 
damaged 
hemisphere 
No 
adverse 
effects 
reported. 
Exhibit 
neuroprotection 
on neurological 
diseases in 
animal models 
i.e Parkinson 
disease 
UCMSCs 
6 × 10^5 hUC-
MSCs 
Chang-
Ching 
et al, 
2008 
Rat 
Allogeneic 
transplanted 
into the 
lesion site 
No 
adverse 
effects 
reported. 
Improvements 
in locomotion  
UCMSCs 
5 × 10^5 hUC-
MSCs 
 
2.  
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Study Objectives 
2.1.1 Primary Objective 
- 
To compare the safety of UCMSCs and BMMSCs administered intravenously in 
patients with chronic inflammation due to metabolic syndrome. 
 
2.1.2 Secondary Objectives 
- 
To demonstrate the efficacy of UCMSCs and BMMSCs administered intravenously in 
patients with chronic inflammation due to Metabolic Syndrome as assessed by (see 
Table 9 in Section 2.2.2): 
▪ symptom related quality of life  
▪ cardiovascular status  
▪ inflammatory cytokines 
▪ endothelial function 
▪ lipid profile 
▪ glucose homeostasis 
▪ 1 year survival 

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2.2 
Study Endpoints 
 
2.2.1 Primary Endpoints (Safety) 
 
Safety will be assessed as the incidence within one month after an infusion of any 
treatment emergent serious adverse events (TE-SAEs), defined as one or more of 
the following events that: is life-threatening event (e.g., stroke or non-fatal 
pulmonary embolism); requires inpatient hospitalization or prolongation of existing 
hospitalization (e.g., for worsening dyspnea); results in persistent or significant 
disability/incapacity; results in death; or leads to clinically significant untoward 
laboratory test result(s) or medical condition(s), determined per Investigator’ 
judgments. 
 
2.2.2. Secondary Endpoints (Efficacy) 
 
(Assess  at  Baseline,  Week 2, Month 1, Month 3, and Month 6 following  IV  
allogeneic  MSC  infusion). Assess EPC-colony forming units (CFUs) 2. Assess 
circulating inflammatory markers (IL-1, IL-6, TNFα, and CRP) 3. Assess  circulating  
angiogenic  factors  known  to  mobilize  and  recruit  EPCs  (VEGF, SDF-1α, and 
SCF)4. Assess FMD%. 
3. 
STUDY DESIGN 
3.1 
Description of the Study 
 
A Pilot Phase will be performed to test the safety of dose and volume of cells administered 
via peripheral intravenous infusion. The first three (3) subjects in-group 1 (UCMSCs) will 
be treated first and safety will be fully assessed.  Only if there is no evidence of treatment 
emergent SAEs in Group 1, treatment of subjects in Group 3 be undertaken.  
The subjects in the high dose (Groups 3 & 4) will not be treated until the subjects in the low 
dose (Groups 1 & 2) have completed their one-month follow-up assessments and safety 
measures have been reviewed to confirm that there have been no treatment emergent 
SAE’s. Treatment emergent SAE’s, defined as the composite of: death, non-fatal pulmonary 
embolism, stroke, hospitalization for worsening dyspnea and clinically significant 
laboratory test abnormalities, prior to proceeding with the treatment of further subjects.   
Subjects in each pilot phase group (Group 1, 2, 3 and 4) will not be treated less than 5 days 
apart. 
Subjects in the pilot phase will receive a telephone call 5 days post infusion (+/- 1 day) to 
review adverse events. 
The randomized portion of the study will be conducted after a full review of the safety data 
from the Pilot Phase by the DSMB. 

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Following the pilot study (12 subjects), thirty (30) subjects that meet inclusion criteria will 
be scheduled to undergo peripheral intravenous infusion. 
 
3.2. 
RANDOMIZATION STUDY 
 
This Phase I/II, randomized, blinded, placebo-controlled study is designed to evaluate the 
safety and tolerability of UCMSCs versus BMMSCs in subjects with chronic inflammation 
due to the metabolic syndrome and to explore potential efficacy at baseline, 3 and 6 
months. 
 
In the randomized phase of the trial, product will be prepared by ISCI GMP laboratory 
personnel. The selected personnel will not have contact with the investigators or subjects 
for this trial.  At the time of administration, opaque tubing will be used to maintain double 
blinding. Treatments will be administered once and will consist of 1 x 108 (100 million) 
UCMSCs, 1 x 108 (100 million) BMMSCs or placebo.  After each infusion, subjects will be 
monitored for immediate complications.   
Continued safety and tolerability with review of adverse events (AEs) will be monitored at 
each visit.  Efficacy parameters (6MWT and QOL questionnaires) will be assessed at various 
study visits.  Clinical laboratory tests to assess safety will be performed at every clinic visit, 
excluding the baseline visit.   
 
4.  
SUBJECT SELECTION 
 
4.1  
Inclusion Criteria 
 
In order to participate in this study, a subject MUST: 
 
1. Provide written informed consent 
2. Subjects age > 21 and < 95 years at the time of signing the Informed Consent Form.  
3. Each subject must have endothelial dysfunction. Endothelial dysfunction criteria: 
impaired flow-mediated vasodilation (FMD < 7%). 
4. At the time of enrollment, each subject must meet at least 3 out of the 5 criteria under 
the harmonized definition of the metabolic syndrome, consisting of the following: 
 
Table 10. Criteria for the Metabolic Syndrome 
Measure 
Categorical Cut-Off Points 
Alternative Indicators 
Waist circumference US defined:  ≥ 102 cm (males) 
or ≥ 88 cm (females) 
Ethnic and country-specific 
definitions 
Elevated triglycerides ≥ 150 mg/dL (1.7 mM) 
Drug treatment for elevated 
triglycerides 
Reduced HDL 
Males:  <40 mg/dL (1.0 mM) 
Drug treatment for reduced 

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Females:  <50 mg/dL (1.3 mM) HDL-C 
Elevated blood 
pressure 
Systolic ≥ 130 mm Hg and/or 
Diastolic ≥ 85 mm Hg 
Antihypertensive drug 
treatment for a history of 
hypertension 
Elevated fasting 
glucose 
≥ 100 mg/dL 
Drug treatment of elevated 
glucose 
 
 
4.2  
Exclusion Criteria 
 
In order to participate in this study, a subject MUST NOT: 
 
1. Be a female who is pregnant, nursing, or of childbearing potential while not practicing 
effective contraceptive methods. Female subjects must undergo a blood or urine 
pregnancy test at screening and within 36 hours prior to infusion. 
2. Inability to perform any of the assessments required for endpoint analysis. 
3. Active listing (or expected future listing) for transplant of any organ. 
4. Clinically important abnormal screening laboratory values, including but not limited 
to: hemoglobin <8 g/dl, white blood cell count <3000/mm3, platelets <80,000/mm3, 
INR > 1.5 not due to a reversible cause (i.e. Coumadin), aspartate transaminase, alanine 
transaminase, or alkaline phosphatase > 3 times upper limit of normal. 
5. Serious comorbid illness that, in the opinion of the investigator, may compromise the 
safety or compliance of the subject or preclude successful completion of the study.  
Including, but not limited to: HIV, advanced liver or renal failure, class III/IV congestive 
heart failure, myocardial infarction, unstable angina, or cardiac revascularization 
within the last six months, or severe obstructive ventilatory defect.  
6. Have known allergies to penicillin or streptomycin.  
7. Be a solid organ transplant recipient. This does not include prior cell-based therapy 
(>12 months prior enrollment) bone, skin, ligament, tendon or corneal grafting. Have a 
history of organ or cell transplant rejection. 
8. Have a clinical history of malignancy within 3 years (i.e., subjects with prior 
malignancy must be disease free for 3 years), except curatively-treated basal cell 
carcinoma, squamous cell carcinoma, melanoma in situ or cervical carcinoma, if 
recurrence occurs. 
9. Have a non-pulmonary condition that limits lifespan to < 1 year . 
10. History of drug abuse (illegal “street” drugs except marijuana, or prescription 
medications not being used appropriately for a pre-existing medical condition) or 
alcohol abuse (≥ 5 drinks/day for ˃ 3 months), or documented medical, occupational, 
or legal problems arising from the use of alcohol or drugs within the past 24 months  
11. Be serum positive for HIV, hepatitis BsAg or Viremic hepatitis C, and/or Syphilis – 
VDRL (If VDRL is reactive Confirmation with FTA-ABS is needed (Syphilis)). 
12. Be currently participating (or participated within the previous 30 days) in an 
investigational therapeutic or device trial. 
13. Patients with EF<45% (heart failure patients). 

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14. GFR < 35 (chronic kidney disease stage 3 or higher). 
15. Liver disease (elevated LFTs greater than 3x upper limit of normal). 
16. Advanced pulmonary disease (requiring home oxygen and/or less than 1 expected life 
span). 
17. Proliferative diabetic retinopathy if history of diabetes 
18. Hemoglobin A1C greater than 7. 
 
4.3  
Concomitant Treatments, Procedures, and Nondrug Therapies 
 
Subjects will receive standard-of-care medical management of metabolic syndrome, as 
recommended by the ATP III, American Heart Association (AHA) and the National 
Institutes of Health (NIH), and the Endocrine Society.  All concomitant medications 
(prescription or over-the counter) as well as procedures or nondrug therapies (e.g. 
continuous positive airway pressure, pulmonary rehabilitation) will be recorded at the 
initial screening visit and updated at each subsequent visit.   
 
4.4  
Withdrawal Criteria 
 
Subjects will be informed that they have the right to withdraw from the study at any time 
and for any reason without prejudice to future or continued medical care.   Subjects must 
be withdrawn for the following reasons: 
 
- 
Subject request. 
- 
Subject is unable or unwilling to comply with the protocol. 
- 
Medical reasons, at the discretion of the investigator. 
 
Reason for withdrawal will be recorded in the subject’s case report form.  In order to 
adequately monitor for safety and potential efficacy outcomes, subjects who are withdrawn 
for any reason after receiving the first infusion should be encouraged to return for all 
assessments through the end of the study period.  All efforts should be made to continue to 
record safety data and lung function parameters for all withdrawn subjects.  Subjects who 
withdraw for reasons unrelated to the study or study drug (e.g. withdrawal of consent or 
loss to follow-up) may be replaced if deemed necessary to meet study objectives.  
Replacement subjects will be assigned unique identification numbers. 
 
5.   
MESENCHYMAL STEM CELL DONORS 
 
The availability of allogeneic BMMSCs offers the potential for an “off the shelf” product for 
subjects. Significant data has been generated to demonstrate that the allogeneic BMMSCs 
are immune-privileged and can be infused without immune rejection despite disparate 
HLA phenotypes.   
 
Screening of allogeneic donors will follow standard transplant practices and all allogeneic 
donors will meet allogeneic donor eligibility criteria as outlined in 21 CFR Part 1271.   

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Allogeneic donor testing will include anti-HIV-1/2, anti-HTLV I/II, anti-HCV, HIV-1 nucleic 
acid testing, HCV nucleic acid testing, HBsAg, anti-HBc(IgG and IgM), CMV, West Nile Virus 
nucleic acid, T. cruzi ELISA (Chagas), Zika virus, Syphilis – VDRL (Confirmation with FTA-
ABS if needed (Syphilis)) and RPR. Potential donors testing positive for any of these 
infectious diseases with the exception of CMV, will be ineligible.  Bone marrow aspirates 
will be obtained from normal individuals and BMMSCs will be isolated and expanded. 
5.1  
Bone Marrow Aspiration, cord tissue harvest, MSC culture for generation of 
MSCs and Placebo formulation.  
 
A total of approximately 60ml to 120ml of BM will be obtained from a healthy donor’s bone 
marrow. BM will be aspirated from the posterior iliac crest into heparinized syringes.  The 
mononuclear cell fraction will be isolated using a density gradient with Lymphocyte 
Separation Media (specific gravity 1.077).  The low-density cells will be collected and 
washed with Plasma-LyteA containing 1% HSA.  The washed cells will be sampled and 
viable cell numbers determined. The MNCs will be prepared with antibiotic (ie. penicillin or 
streptomycin). The BM mononuclear cells will be seeded into 175 cm2 tissue culture flasks 
in alpha MEM containing 20% FBS. After 14 days of culture, passage zero (P0) cells will be 
harvested by trypsin treatment and expanded into 60 flasks. After 7 to 10 days P1 cells are 
harvested by trypsin treatment (P1 cells). Cells from P1 will be cultured for 7 to 10 days 
and harvested by trypsin treatment and expanded into 180 flasks (P2 cells) with the option 
of expanding them once again, to P3. After 7-10 days P3 cells would be harvested by 
trypsin treatment and cryopreserved.  
 
Before consenting and collecting the umbilical cord tissue, the maternal blood will be 
screened for infectious disease.  
 
Collection of Umbilical Cord Tissue:  The cord will be clamped then cut and 6 to 15 cm of 
the cord will be transferred into a labeled container containing the collection media 
supplemented with antibiotics.  A specialized validated temperature controlled container 
(2–15°C) will be used. The collection kit with the cord will be transported to the processing 
facility within 36 hrs. Upon arrival at the processing facility, the sample will be assigned a 
unique ID that enables the unit to be tracked throughout the process. 
 
The umbilical cord tissue will be enzymatically digested. The digested cells will be washed 
and cultured. An expansion process of 3 passages will take place followed by 
cryopreservation.  
 
Placebo will be formulated as following: 
 
The placebo group will receive infusion of PlasmaLyte-A supplemented with 1% HSA. The 
placebo product will undergo QC testing before injection for gram stain and endotoxin. The 
sterility (aerobic, anaerobic and fungal) samples will be taken from final product and 
cultured for 14 days. Product will only be released if testing meets following criteria:   
Gram Stain – Negative  
Endotoxin - < 5EU/kg/hr. 

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5.2  
Donor Eligibility 
 
5.2.1 Bone Marrow Donors Screening and Testing 
 
Donors (male or female) between the ages of 18 to 45 (inclusive) will be screened as 
potential BM donors. Donors will be evaluated by history and physical examination.  The 
history will include: 
 
• 
History of malignancy 
• 
Bleeding abnormalities 
• 
Prior deep venous thrombosis 
• 
Known cardiac or pulmonary conditions 
• 
Prior blood transfusions 
• 
Vaccinations 
• 
Questions to identify persons at risk of infectious disease transmission, including 
Zika virus 
• 
Questions to identify persons at risk of transmitting hematological or 
immunological disease 
• 
A physician will administer the National Marrow Donor Program (NMDP) 
Questionnaire (a donor health history screening questionnaire).  
 
a. The physical examination will include evaluation for potential risks associated with 
the BM aspiration procedure.  Prospective donors will have infectious disease 
testing including: 
• 
Hepatitis B surface antigen (HBsAg) 
• 
Hepatitis B core antibody (HBcAb) 
• 
Hepatitis C virus antibody (HCV Ab) 
• 
Human Immunodeficiency Virus (HIV) antibody (HIV 1/2) 
• 
Cytomegalovirus antibody (CMV) 
• 
HCV/HIV Nucleic Acid test 
• 
West Nile Virus Nucleic Acid test 
• 
Rapid Plasma Reagin (RPR) or VDRL (if VDRL reactive confirmation with FTA-
ABS is needed (Syphilis)) 
• 
Human T-lymphotropic Virus I/II (HTLV I/II) 
• 
T. cruzi ELISA test (Chagas disease) 
• 
Zika Virus testing (RNA qualitative Real Time RT-PCR, Serum/Urine or Zika 
Virus Antibody (IgM), MAC-ELISA) 
 
 
If a donor tests positive for CMV the donor may still be able to participate. 
 
b. Prospective donors will also have the following tests: 

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• Complete blood count with differential 
• Complete metabolic panel, magnesium, calcium, and uric acid 
• Urinalysis 
• Serum pregnancy test (Female only) 
 
c. Eligibility Criteria for Normal Donors will include: 
• Male and female gender 
• No history of malignancy  
• No active coagulopathy and/or hypocoagulable state 
• No history of cardio/pulmonary conditions 
• Negative tests for Hepatitis B, Hepatitis C, RPR orVDRL, Chagas, HIV 1, 2, HTLV 
I/II and NAT for HCV, HIV, Zika Virus and WNV.   
• Hemoglobin > 13.0 g/dL if male; and if female donor hemoglobin > 11.0 g/dL 
• Platelet count 140,000 to 440,000/ul 
• WBC 3.0 to 11.0 K/ul 
• No anomalies on the CBC and differential suggestive of a hematopoietic disorder 
or infection 
• Creatinine <1.5 mg/dL 
• ALT< 112 IU/L 
• Bilirubin < 1.5 mg/dL 
• No diabetes 
• Systolic blood pressure < 170 
• Diastolic blood pressure < 90 
• No history of autoimmune disorders 
• Negative serum or urine pregnancy test for female donors 
• Body Mass Index (BMI) < 30 
Female donors would need to be screened for pregnancy as the procedure may be an added 
risk to a fetus. 
 
5.2.2 Umbilical Cord Tissue Donor Screening and Testing 
 
Upon consent the maternal blood will be screened for infectious disease prior to collecting 
the umbilical cord tissue. This will prevent the introduction, transmission, and spread of 
communicable disease agents and diseases. 
All Umbilical cord tissue donors between the ages of 18 to 35 must be tested and screened 
for the following: 
a. Donor screening and reviewing of relevant medical history records and social 
history for risk factors will be evaluated by history and physical examination.  
The history will include: 
• History of malignancy 

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• Bleeding abnormalities 
• Prior deep venous thrombosis 
• Known cardiac or pulmonary conditions 
• Prior blood transfusions 
• Vaccinations 
• Questions to identify persons at risks of infectious disease transmission 
• Questions to identify persons at risk of transmitting hematological or 
immunological disease 
 
b. Umbilical donors are tested for transmissible infectious diseases as follow 
(results from any viral or infections agent testing must be negative): 
• Hepatitis B surface antigen (HBsAg) 
• Hepatitis B core antibody (HBcAb) 
• Hepatitis C virus antibody (HCV Ab) 
• Human Immunodeficiency Virus (HIV) antibody (HIV 1,2) 
• Cytomegalovirus antibody (CMV) Immune Screen (total immunoglobulin, 
including IgG and IgM). Positive samples are tested for CMV DNA. 
• HCV/HIV Nucleic Acid test 
• West Nile Virus Nucleic Acid test 
• Rapid Plasma Reagin (RPR) 
• Human T-lymphotropic Virus I/II (HTLV I/II) 
• T. cruzi ELISA test (Chagas disease) 
• Zika Virus Testing 
• VDRL (confirmation with FTA-ABS if needed (Syphilis)) 
 
 
Results from any viral or infectious agent testing must be negative. 
c. Eligibility Criteria for Umbilical Donors will also include: 
• Female gender 
• No history of malignancy  
• Cancer 
• Bleeding abnormalities 
• Neurological diseases  
• Blood and bleeding disorders, including sickle cell disease 
• History of autoimmune disorders 
• No family history (biologic mother, father or sibling) of genetic disorder that 
may affect the recipient. 
• Negative tests for Hepatitis B, Hepatitis C, RPR, VDRL, Chagas, HIV ½, HTLV 
I/II and NAT for HCV, HIV, Zika Virus and West Nile Virus.   
• No diabetes (gestational diabetes is not an exclusion criteria) 
 
5.3  
Bone Marrow Donor Consent 
 

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Informed consent will be obtained from all potential donors. The procedure will be 
explained in terms the donor can understand, and will include information about the 
significant risks of the procedure. Potential donors will have an opportunity to ask 
questions, and the right to refuse or withdraw consent, and access to the results of all tests. 
 
Donors will need to have virology’s redrawn if BMA procedure not completed 7 days from 
the initial virology results. 
 
5.4  
Follow-up Schedule for Bone Marrow Donors  
 
After discharge from the hospital, the bone marrow donor will be contacted by the study 
team with a follow-up telephone call to determine the well-being, health status of the donor 
and/or if any adverse events have occurred.    Attempts should be made to follow-up via 
phone within a week of the BMA procedure. The donor will be provided with contact 
telephone numbers in the consent form for any questions or comments.  
 
5.5 
Biomarker Assessment for Bone Marrow Donors 
 
A separate blood sample of about 10mL will be obtained at the donation visit for gene 
expression profiling. All samples will be identified so that they can be linked to individual 
subjects.  These samples may be stored indefinitely.  Individual results will not be returned 
to the subject or the study physician. The samples will be linked to subjects, but there will 
be no recontact. Data presented in publications will not contain individual subjects’ gene 
expression or clinical characteristics or outcomes; only aggregate data from the entire 
study will be disclosed.   
 
6.  
TREATMENT OF SUBJECTS 
 
6.1  
Study Investigational Product 
 
The investigational product (IP) consists of BMMSCs obtained from donor bone marrow. 
Screening of allogeneic donors will follow standard transplant practices and all allogeneic 
donors will meet allogeneic donor eligibility criteria as outlined in 21 CFR Part 1271.  
 
The investigational product (IP) consists of UCMSCs obtained from donor cord tissue. 
Screening of allogeneic donors will follow standard transplant practices and all allogeneic 
donors will meet allogeneic donor eligibility criteria as outlined in 21 CFR Part 1271. Cord 
tissue will be obtained from normal donors.  
 
6.2  
Dosing 
 
The allogeneic BMMSCs or UCMSCs will be derived from normal donors meeting criteria for 
allogeneic unrelated human bone marrow stem cell source or human cord tissue 
manufactured by the ISCI Clinical Research Cell Manufacturing facility at the University of 
Miami. 

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6.3  
Dosage Rationale 
 
A safety profile for IV infusion of BMMSCs and UCMSCs is based on results from previous 
completed toxicology results76. The results from previous studies demonstrate that the 
product can be administered intravenously without toxic events at up to 65 x 106hMSC/kg 
dose delivered in one bolus infusion or at 100 x 106 hMSC/kg cumulative dose delivered by 
5 infusions (20 x 106hMSC/kg per infusion). 
 
The evidence supports the conclusion that it is feasible to dose subjects in this study based 
on a standard dose of hMSCs rather than per kilogram of body weight. The total cell 
number corresponds to a range of 1.3 - 4.4 x 106 hMSCs per kg per infusion for subjects 
with 45 to 150kg body weight. 
 
Therefore, results from previous trials support the rationale on the safety and potential 
efficacy of the selected maximum dose of 100 x106 allo-hMSCs. 
 
6.4  
Administration Rate 
 
Prior clinical trials have used rates up to 30×106 hMSC/min where no infusion related 
toxicity was observed.  
 
In the proposed study, the cell dose to be delivered is 20 or 100 million cells in 80 mL Cells 
will be delivered at a rate of 2mL/min, and delivered at a maximum rate of 2.5×106 
hMSC/minute and will last approximately 40 minutes for both doses. 
 
The infusion bag will be flushed with an additional 25 ml of 0.9% normal saline at the 
completion of allo-hMSC infusion and delivered at a rate of 2ml/min. 
 
 
6.5  
Concomitant Therapy 
 
6.5.1 Permitted therapy 
 
Concomitant medications will be recorded on the case report form (CRF), which includes 
all FDA-approved medications, therapies, and dietary supplements. 
 
6.5.2 Excluded therapy 
 
Medications and therapies not approved by the FDA are prohibited for the duration of this 
trial, including participation with any investigational drug or device. 
 
6.5.3. Subject monitoring 
 
All aspects of the study will be conducted in accordance with Good Clinical Practice (GCP) 
as described in the ICH Guideline (CFR ICH Selected Regulations and Guidance for Drug 

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Studies, CFR Title 21 Food and Drugs Revised as of April 1, 2016) all applicable national 
and local regulations. Monitoring will be conducted by a qualified outside source at the 
study site. 
 
Monitoring of key safety endpoints (refer to Table 8 in section 2.2.1) will be conducted.  
6.6 Blinding and Un-blinding 
 
Subjects will be randomized into active groups. Only designated technicians in the ISCI Cell 
Processing Laboratory will be unblinded to treatment. The investigator, study staff, subject 
and anyone involved in the care of the subject will not be made aware of the assigned 
treatment regimen. Before dispensing the investigational product, Cell Therapy Lab staff 
will confirm the CMV status of eligible recipient. This information will be used to select 
Allo-BM and UC MSC product. CMV status of the recipient and donor of the Allo-BM and UC 
MSC product will be matched. CMV positive Allo-BM or UC MSC product will only be 
infused to a CMV positive recipient. All CMV negative recipients will receive CMV negative 
Allo-BM or UC MSC product134. 
 
The designated cell-processing technicians will prepare both (BM and UC) the allogeneic 
MSCs infusions. The investigational agent infusions will be prepared in identical infusion 
bags and labeled with the identical investigational drug labels. A brown plastic slip cover 
will be placed over the infusion lines as well as the bags to maintain the blind. The 
designated technicians in the ISCI Cell Processing Laboratory (or designee) will be 
responsible for maintaining the investigational product records including randomized 
treatment assignments by subject identification. 
 
If for important medical reasons un-blinding is thought to be necessary, the Investigator 
may identify the treatment assignment by obtaining the randomization assignment by 
contacting the Director of Experimental and Clinical Cell Based Therapies at ISCI who is 
responsible for maintaining randomization records for all subjects. 
 
6.7 
Study Investigational Therapy Management 
 
6.7.1 Investigational Product Labeling and Storage 
 
The product label contains the elements required by the CFR and other national and local 
authorities for investigational products. ISCI CMP will directly store and deliver the 
designated cell processing technologist in the CPL, and will be kept cryopreserved in a 
liquid nitrogen vapor phase until shortly before administration and must be stored in a 
securely locked enclosure. Access is strictly limited to unblinded CPL personnel prior to 
preparation for infusion. After preparation for infusion, the Investigator and his or her 
designees are permitted to administer the Investigational Product only to subjects 
participating in this protocol. 
 
6.7.2 Investigational Product Accountability Procedures 
 

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In accordance with all applicable regulatory requirements, the Cell Processing Laboratory 
will maintain a record of the investigational products BMMSCs or UCMSCs received, 
dispensed, administered, destroyed, or returned. The final disposition of all unused, empty, 
and partially used Cryocyte™ bags will be handled in accordance with the drug preparation 
manual.  
 
Only unblinded personnel may access accountability records until the study blind has been 
broken. 
7. 
STUDY PROCEDURES 
7.1. 
Time and Events Schedule 
The Time and Events Schedule for the conduct of this study is shown in Table 11

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Schedule of Assessments  
Table 11: Time and Events Table 
Subjects in the pilot phase will receive a telephone call 5 days post infusion (+/- 1 day) to review adverse events 
 
1- Weight, Height (will only be collected at screening) 
2- See table 12 for specific tests done at each time point  
3- Brachial ultrasound to assess endothelial function should be completed in the morning prior to 12p.m. Instruction for completing this 
assessment are outline in Appendix 3 of this protocol 
4- Dobutamine Stress Echocardiogram (DSE) will be performed, at screening and at the Month 6 follow-up visit. Instructions for completing the 
(DSE) are outlined in Appendix 2 of this protocol. If the stress test needs to be stopped due to unforeseeable side effects and cannot be completed on a 
subject, this will not prevent them from being able to take part in the study. 
. 
 
VISIT 
Screening 
+ 45 days 
Baseline 
(0 to -4 
weeks prior 
to Day 0) 
Day 
0 
 
Week 2 
(Day 14) 
 
± 2 days 
Month 1 
(Day 30) 
 
±1 weeks 
Month 3 
(Day 90) 
 
±4 weeks 
Month 6      
(Day 180) 
 
±6 weeks 
Month 12 
(Day 365) 
 
±2 weeks 
Informed Consent 
X  
 
 
 
 
 
 
 
Full Medical History  
X  
 
 
 
 
 
 
 
Physical Exam 
X  
X  
X  
X  
X  
X  
X  
X 
Vital Signs1 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead (ECG) 
X  
X  
X  
X  
X  
X  
X  
X 
Concomitant Medications 
X  
X  
X  
X  
X  
X  
X  
X 
Randomization 
 
X  
 
 
 
 
 
 
Infusion Treatment (IP) 
 
 
X  
 
 
 
 
 
6 Minute Walk Test 
 
X  
 
 
 
X  
X  
 
4 Meter Gait Speed Test 
 
X  
 
 
 
X  
X  
 
QOL Questionnaires (EQ-5D, SF-36, IIEF 
(Male), SQOL-F(Female)) 
 
X  
 
 
X  
X  
X  
 
 Laboratory Testing2 
 
 
 
 
 
 
 
 
Review Adverse Events 
 
X 
X  
X  
X  
X  
X  
X  
Brachial Ultrasound 3 
X  
X  
 
 
 
X  
 
 
Dobutamine Stress Echo (DSE)4 
X  
 
 
 
 
 
X  
 

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Schedule of Laboratory Testing  
Table 12: Time and Events Table 
VISIT 
SCR 
BSL 
DAY 0 
W2 
M 1 
M 3 
M 6 
M 12 
Standard Labs 
CBC with Differential 1 
X 
 
X 
X 
X 
X 
X 
 
Comprehensive Metabolic Panel 2 
X 
 
X 
X 
X 
X 
X 
 
PT, INR, PTT 
X 
 
 
 
 
 
 
 
Uric Acid, Pro BNP, hsCRP, IL6, Fib, D-dimer, TNFa, 
X 
 
X 
X 
X 
X 
X 
 
Lipid Profile 3 
X 
 
X 
X 
X 
X 
X 
 
Urinalysis 
X 
 
X 
 
X 
X 
X 
 
HbA1c 
X 
 
 
 
X 
X 
X 
 
Pregnancy (childbearing women)4 
X 
 
X 
 
 
 
 
 
Biomarkers / 
Immune 
SST / PRA5 
 
 
X 
 
 
 
X 
 
MNCs6 
 
 
X 
X 
X 
X 
X 
 
EPCs 
Endothelial Blood Samples7 
 
X 
 
 
 
X 
 
 
Gene Expression 
DNA8 
 
 
X 
 
 
 
 
 
RNA 
 
 
X 
 
 
 
X 
 
Viral Serology 
Infectious Disease Tests9 
X 
 
 
 
 
 
 
 
1. Complete Blood Count with Differential - WBC, RBC, hemoglobin, hematocrit, MCV, and platelets; Diff: neutrophils, lymphocytes, monocytes, 
eosinophils, and basophils.  
2. Complete Metabolic Panel – glucose, sodium, potassium, chloride, biocarbonate, blood urea nitrogen, creatinine, total protein, albumin, alkaline 
phosphatase, total bilirubin (fractionate if total >1.5 times normal), alanine transaminase (ALT), aspartate transaminase (AST), and GFR. 
3. Lipid Profile: Triglyceride levels, Total cholesterol, LDL levels, and HDL levels 
4. Pregnancy Serum β HCG: will be completed within 36 hours prior to infusion 
5. SST: (2 Gold or Tiger top tube) Transcriptomic/proteome (RNA, mRNA, protein samples, and telomerase, akt); growth factors (sdf-1, notch); 
functional assays (cell-growth rate, VEGF, and CFU assays) and more. 
6. MNCs: (2 Green top tube) CD3*CD25* or CD3*CD69* and more 
7. Endothelial Blood Samples: (5 Lavender top tubes) Endothelial Progenitor Cell- Colony Forming Units (EPC-CFU). Must be performed on the 
same day as the day as the brachial artery ultrasound.  
8. Genetic Testing: Deoxyribonucleic acid (DNA) to be collected at one time point only. 
9. Infectious disease tests – HIV, HIV 2, Hep B (HBsAg, HBs Ab, HBc Ab), Hep C (Anti-HCV), VDRL/Syphilis (reflex FTA Ab), and CMV. 

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7.1.1  Remote Visits 
Since trial participants may not be able to come to the investigational site for protocol 
specified visits during the “Coronavirus disease 2019” (Covid-19) pandemic, alternative 
methods for assessments (e.g., phone contact, virtual visit, alternative location for 
assessment, including local labs or imaging centers) could be implemented when necessary 
and feasible, and would be sufficient to assure the safety of trial participants. Assessments 
can be completed as follows: 
- 
Physical Examination – Can be completed via telemedicine using a virtual platform. 
- 
Vital Signs and 12-lead EKG – If subject has completed an EKG or vital signs within 
the protocol specified time window with their PCP or any other treating physician, a 
copy can be requested. Alternatively, subjects may record and report their own vital 
signs or EKG using home testing equipment (such as thermometer, automated blood 
pressure monitor, pulse oximeter, wearable health devices, or other method for 
recording vital signs. 
- 
Questionnaires, concomitant medications and review of adverse events – may be 
completed by study team via email, phone contact, virtual visit or alternative 
methods. 
- 
Laboratory assessments – A copy of SOC labs (urinalysis, hematology, chemistry, Hg 
A1C , lipid profile as well as  any labs required by the protocol for particular time 
point) may be obtained from PCP or treating physician if done within the protocol 
specified time window.  If  participant has not completed any laboratory assessment 
they may complete them in any local laboratory facility.  
- 
Brachial Artery Ultrasound, 6 minute walk test, 4 meter gait speed test, Dobutamine 
Stress Echo, Immune Monitoring, EPC-CFUs and Biomarkers Assessment – if 
participant is willing to come to site to complete these assessments, all necessary 
safety precautions will be taken. Study team will  provide the subject with a mask 
and gloves upon arrival to the site. If  subject prefers to complete this assessment at 
another time, the study team  must document if the assessment will be completed 
out of the protocol specified time window and report to the regulatory authorities 
accordingly. 
7.2  
Study Phases and Visits 
7.2.1 Screening Visit 
See Table 11 for the procedures and assessment to be performed during the screening visit 
of the study. All screening visit test and procedures will occur upon signing the informed 
consent form (ICF). No screening exams will take place until the subject is fully informed of 
the research and signs the consent form. The tests may take place over several days and 
will need to be completed prior to performing the baseline visit. There will be up to a 45-
day window from the time the subject signs the informed consent form to the baseline visit 
to complete screening procedures. 
A subject may be rescreened based on the Investigators judgement and will at a minimum 
need to reconsent and complete screening laboratory tests. The subject will remain with 
the same subject number throughout this process. 

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7.2.2 Baseline Visit 
See Table 1 for the procedures and assessment to be performed during the baseline visit of 
the study. This visit will occur after all screening tests are completed and it has been 
determined that the subject meets eligibility criteria. This visit should occur within 4 weeks 
prior to Day 0 (the infusion visit). 
7.2.3 Day 0 Visit 
See Table 11 for the procedures and assessment to be performed during the Day 0 visit of 
the study. The Day 0 visit will occur after all baseline tests are completed and it has been 
determined that the subject remains eligible. Once the subject is deemed eligible to 
continue in the study the subject will be administered the investigational product. 
7.2.4 Week 2 Visit 
See Table 11 for the procedures and assessment to be performed for the week 2 visit of the 
study. Outpatient visits should be completed as close to the scheduled visit dates as 
possible. There will be a window of +/-2 days for the week 2 study visits. 
7.2.5 Month 1 Visit 
See Table 11 for the procedures and assessment to be performed for the Month 1 study 
visit. Outpatient visits should be completed as close to the scheduled visit dates as possible. 
There will be a window of +/-1 weeks for the Month 1 study visits. 
7.2.6 Month 3 
See Table 11 for the procedures and assessment to be performed for month 3 study visit. . 
Outpatient visits should be completed as close to the scheduled visit dates as possible. 
There will be a window of +/-4 weeks for the Month 3 study visit.   
7.2.7 Month 6 - Month 12 Visit (Final Study Visit) 
See Table 11 for the procedures and assessments to be performed for Month 6 through 
month  12 visit  of the study. Outpatient visits should be completed as close to the 
scheduled visit dates as possible. There will be a window of ±6 weeks for the Month 6, and 
±2 weeks for the Month 12 study visits. 
7.3 Assessment Details 
 
7.3.1 Physical Exam 
A complete medical history will be conducted during screening testing including: vital 
signs, height and weight; medical, surgical, and smoking history; and review of current use 
of prescription and OTC medications. Similar physical exams will be conducted at each 
additional clinic visit during the study including vital signs, weight, review of AEs, and 
concomitant medications. 
 
7.3.2 Vital Signs 
Vital sign measurements will be performed at least once on each study visit up to time of 
discharge. These measurements will consist of oxygen saturation, weight, respiratory rate, 
heart rate, blood pressure, and temperature. Respiratory rate, heart rate, and blood 
pressure should be measured in a sitting position after 5 minutes of rest. Height will only 
be collected at the screening visit. 

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7.3.3 Dobutamine Stress Echocardiography (DSE) 
A Dobutamine Stress Echocardiography will be performed twice during the study, once at 
screening and at the Month 6 follow-up visit. This exam will assist in mimicking the effect 
of exercise on subjects to assess the heart muscle and ejection fraction when under stress. 
(refer to appendix 2) 
 
7.3.4 Flow Mediated Diameter percent change (FMD%)   
A Flow Mediated Diameter percent change will be performed three times during the study, 
once at screening, baseline, and at the Month 6 follow-up visit. This exam will assess 
vascular function. All measurements of the brachial artery diameter and FMD will be 
performed in the morning, in a quiet and dark room. (refer to appendix 3) 
7.3.5 Laboratory Testing 
• Gene Expression 
A separate blood sample of approximately 17mL for gene expression (DNA) 
profiling of WBC (at Day 0 visit) and A separate blood sample of approximately 
5.0mL for RNA expression analysis (at Day 0 and month 6 visits) will be obtained 
from the study participants, as detailed on Table 12. A separate genetic consent 
form is completed by the study participants. 
All samples will be identified so that they can be linked to individual subjects. These 
samples may be stored indefinitely. Individual results will not be returned to the 
subject or the study physician. The samples will be linked to subjects, but there will 
be no recontact. Data presented in publications will not contain individual subjects’ 
clinical characteristics or outcomes; only aggregate data from the entire study will 
be disclosed. 
• Biomarkers/Immune 
The studies planned in this protocol will utilize allogeneic hBMMSCs or hUCMSCs in 
subjects with chronic inflammation due to the metabolic syndrome. The use of an 
allogeneic graft raises the potential of graft rejection through immune cells resulting 
in failure of the therapy. hBMMSCs or hUCMSCs are ideal candidates for allogeneic 
transplantation because they show minimal MHC class II and ICAM expression and 
lack B-7 co-stimulatory molecules necessary for T-cell mediated immune 
responses57, 58. Indeed both types of cells do not stimulate a proliferative response 
from alloreactive T-cells even when the cells have differentiated into other lineages 
or are exposed to proinflammatory cytokines. Previous studies have demonstrated 
that 
MSCs 
have 
significant 
immunomodulatory 
effects, 
inhibiting 
T-cell 
proliferation, prolonging skin allograft survival, and decreasing graft-versus-host 
disease (GVHD). Recently human MSCs were shown to alter the cytokine secretion 
profile of dendritic cells, T cells, and natural killer cells in vitro, inhibiting secretion 
of proinflammatory cytokines (e.g. TNFα, IFN-γ) and increasing expression of 
suppressive cytokines (e.g.IL-10), possibly via a prostaglandin E2 mediated 
pathway.  
 

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In vivo studies of the fate of MSCs have shown that, when transplanted into fetal 
sheep, human MSCs engraft, undergo site-specific differentiation into various cell 
types, including myocytes and cardiomyocytes, and persist in multiple tissues for as 
long 
as 
13 
months 
after 
transplantation 
in 
non-immunosuppressed 
immunocompetent hosts.  Further, in vivo studies using rodents, dogs, goats, and 
baboons demonstrate that allogeneic MSCs can be engrafted into these species 
without stimulating systemic alloantibody production or eliciting a proliferative 
response from recipient lymphocytes. These findings, coupled with our 
demonstration of efficacy of these cells for cardiac repair, solidify the notion of using 
MSCs as an allograft for successful tissue regeneration. 
As part of the CERES protocol we will obtain peripheral blood samples from all 
subjects to evaluate the presence of activated T cells. Two heparinized (green top) 
vacutainer tubes (approx. 15 cc total blood) will be collected at different time points 
during the study (Reference Table 12 for schedule).  Peripheral blood mononuclear 
cells (PBMC) will be isolated from heparinized blood by ficoll sedimentation and will 
be viably cryopreserved for planned assessments of T cell activation. 
Two of the best-accepted markers of T cell activation are CD69 and CD25 (IL-2 
receptor).  We will monitor the activation of T cells by flow cytometric analysis of 
CD3+CD25+CD69+ cells in thawed PBMC. CD69 is an immediate/early marker of 
CD3+ T cell activation while CD25 expression increases within 1-2 days of activation 
and remains sustained over the intermediate-long term during chronic immune 
activation. Given the differences in the kinetics of CD69 and CD25 up regulation, 
assessment of both activation phenotypes (CD3+CD69+ and CD3+CD25+) will 
maximize the sensitivity of detection of T cell activation following allogeneic MSC 
infusion. 
Additionally, in female subjects who receive allogeneic hBMMSCs or hUCMSCs, the 
stored baseline serum will be analyzed to evaluate the antibody responses to HLA 
and H-Y antigens. 
These samples will 1) provide storage of critical biomaterials derived from subjects 
enrolled in CERES 2) provide long-term integrity of these biospecimens and 
samples, and 3) provide management of samples for postdoctoral studies of 
immunologic, immunohistochemical, cellular, and molecular analyses of collected 
samples; as well as cell-surface markers (CXCR4, C-Kit, & Connexin 43), 
transcriptomic/Proteome (DNA, RNA, miRNA, protein samples, and telomerase, 
akt),  growth factors (Sdf-1, notch,), functional Assays (cell growth rate, VEGF, and 
CFU assay),  CD3, CD25, CD69,  Inflammatory (IL-1, TGF-) , (but not limited to these 
biospecimens) will be used for research purposes only, will be stored without 
personal identifying information, and will be shared with approved researchers who 
will conduct studies to improve the understanding of the effects of cell therapies 
and/or of metabolic syndrome. 
• EPCs 
Blood collection will be performed to assess endothelial function in the metabolic 
syndrome population at baseline and 3 months post stem cell infusion. This will 

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help provide cumulative data in assessing whether or not stem cell infusion 
improves endothelial function. 
Assay of colony forming units: Fresh blood will be processed for cell culture assays 
for endothelial progenitor stem cells colonies counting (a 5 days’ protocol). Fifty 
milliliter of blood will be processed; peripheral-blood mononuclear cells will be 
isolated by Ficoll density-gradient centrifugation, will be washed twice in phosphate 
buffered saline with 5% fetal bovine serum and re-suspended in media (EndoCult 
basal media with supplements; StemCell Technologies, Vancouver, British Columbia, 
Canada) for EPC colony-forming assay. Cells will be planted on human fibronectin-
coated plates (BIOCOAT; Becton Dickenson Labware, Bedford, Massachusetts) at a 
density of 5X106 cells/well and incubated at 370C in humidified 5% CO2. After 48 
hours, the non-adherent cells will be re-plated onto fibronectin-coated 24 well 
plates at a density of 1X106 cells/well. After 5 days, colony forming units (defined as 
a central core of rounded cells surrounded by elongated and spindle-shaped cells) 
will be counted manually in 8 wells out of a 24-well plate. 
8.   
SAFETY 
8.1  
Safety Variables 
 
1. 
Vital signs 
2. 
Physical examination 
3. 
Clinical laboratory tests 
4. 
Adverse events 
8.1.1  Laboratory Evaluations 
 
At screening, the HIV-1 and HIV-2 tests, Syphilis – VDRL (If VDRL is reactive Confirmation 
with FTA-ABS is needed), CMV, hepatitis screen and β-HCG serum pregnancy tests (only for 
women of childbearing potential) will be performed locally at the study site. Laboratory 
safety tests will consist of the following: 
 
Serum chemistry: sodium, potassium, chloride, BUN, creatinine, glucose, calcium, 
AST/SGOT, ALT/SGPT, carbon dioxide, total bilirubin (fractionate if total >1.5 times 
normal), alkaline phosphatase, albumin, fibrinogen, IL6, D-Dimer, Coagulation 
studies 
Hematology: hemoglobin, hematocrit, platelets, WBC, RBC,  
 
The Investigator will review all clinically relevant laboratory results requested in the 
protocol. The diagnosis associated with any clinically significant laboratory deviations 
should be recorded as an AE and should indicate the underlying abnormality or diagnosis 
(such as renal insufficiency) as opposed to the observed deviation in laboratory results 
(such as elevated creatinine). If there is no underlying abnormality linked to a clinically 
significant abnormal laboratory value, the observed deviation should be reported as the 
AE. 

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8.1.2 Pulse Oximetry 
Pulse oximetry will be used to observe oxygen saturation when measuring vital signs. Pulse 
oximetry will also be used throughout infusions and 2 hours following infusions. Subjects 
should have a resting oxygen saturation of ≥93% in order to be randomly assigned. 
Subjects requiring oxygen, need the peripheral artery oxygen saturation (SaO2) to be ≥93% 
when given a maximum of 2L/minute supplemental O2 via nasal cannula. Infusion toxicity 
will be assessed based on decreases in oxygen saturation during infusion.  The infusion will 
be stopped if the oxygen saturation does not return to >93% within 3 minutes of initiating 
supplemental oxygen or if the subject requires greater than 2L/min supplemental oxygen 
to achieve the required saturation of >93%. If this occurs then subjects will be admitted to 
the hospital for observation. 
 
8.1.3 Pregnancy 
There is no information regarding allogeneic BMMSCs or UCMSCs and their effects or 
potential risks to a fetus or unborn child.  The Principal Investigator and DSMB must be 
notified within twenty-four hours of investigator’s awareness of the pregnancy via 
facsimile if a study subject becomes pregnant during the study. Any one of the enumerated 
contraceptive items will be acceptable for meeting the studies contraceptive requirements 
as listed in this section. Females will be defined as non-childbearing potential if surgically 
sterilized (i.e. bilateral tubal litigation, bilateral oophorectomy, or complete hysterectomy) 
or post-menopausal (defined as 12 months no menses with an alternative medical cause 
and with a follicle stimulating hormone (FSH > 25.8 IU/L). Non-sterilized males who are 
sexually active with a female partner of childbearing potential must use any one of the 
enumerated contraceptive items as listed in section 8.2.2 throughout the study. 
 
Acceptable forms of contraception include: 1) abstinence, 2) condoms (male or female) 
with a spermicidal agent, 3) diaphragm or cervical cap with spermicidal agent, 4) 
intrauterine device (IUD), 5) oral contraceptive, 6) injectable or transdermal hormonal 
contraceptive, 7) successful vasectomy with resulting azoospermia or azoospermia for any 
other reason, and 8) hysterectomy, bilateral oophorectomy, or tubal ligation. 
 
Prior to study enrollment, women of childbearing potential must be advised of the 
importance of avoiding pregnancy during trial participation and the potential risk factors 
for a pregnancy. The subject must sign an informed consent and written authorization for 
use and disclosure of PHI document stating that the above-mentioned risk factors and the 
consequences were discussed with her. 
 
8.1.4 Determination of Infusional Toxicity 
 
Infusional toxicity will be evaluated by continuously monitoring the subject’s vital signs 
and O2 saturation by pulse oximetry from the time of allogeneic BMMSCs or UCMSCs 

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administration until two hours after infusion is complete. Since there is no specific or 
antidotal therapy for AEs arising from allogeneic BMMSCs or UCMSCs, any toxicity that may 
arise during a subject’s participation in this study should be managed with supportive 
measures at the discretion of the treating physician. 
 
8.1.5 Subject Stopping Guidelines 
 
This guideline is to be used to indicate boundaries requiring discussion by the Data and 
Safety Monitoring Board (DSMB) and is designed to assist the independent DSMB in 
overseeing the study. The DSMB may also request additional interim analyses and develop 
other criteria including provision for monitoring of potential late effects to determine when 
to intervene in the enrollment or treatment of subjects in the study. The first more 
conservative stopping guideline is to monitor subjects for unexpected SAEs where there is 
a reasonable possibility that the study product or administration procedure caused the 
event within 30 days of administration including subject death, grade 3 myocardial 
infarction, grade 3 hemodynamically unstable ventricular tachycardia or grade 3 LV 
perforation.  Study accrual and further treatment of subjects will be put on hold if any 
subjects experience one of these events.  The DSMB will be notified within 24 hours of the 
occurrence of these events and will be convened within 3 business days to review the event 
and study. 
 
The following are subject stopping guidelines: 
 
5. Any subject who develops persistent (that is, still existing more than 3 hours after 
the end of IP infusion) cardiorespiratory signs or symptoms (for example, shortness 
of breath, tachypnea, tachycardia, Bradycardia, hypotension, or palpitations) will 
continue with all scheduled follow-up if such follow-up is considered safe in the 
opinion of the Investigator. 
 
6. Any subject whose infusion is stopped due to cardiorespiratory distress will receive 
no further IP infusions but will continue with all scheduled follow-up if such follow-
up is considered safe in the opinion of the Investigator. 
 
7. Any subject who develops any sign or symptom that, at the discretion of the 
Investigator, warrants the discontinuation of infusion will receive no further IP 
infusions but will continue with all scheduled follow-up if such follow-up is 
considered safe in the opinion of the Investigator. 
 
8. Infusion of the IP may be stopped if there is an adverse event that the Investigator 
believes is related to the IP or if there is an issue with the IP infusion. 
 
9. The proportion of subjects experiencing TE-SAE as defined in Section 2.2.1 will be 
monitored within 30 days of infusion. This guideline is designed to assist the 
independent DSMB in overseeing the study and indicate boundaries needing 
discussion by the DSMB. The DSMB may also request additional interim analyses 

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and develop other criteria including provision for monitoring of potential late 
effects to determine when to intervene in the enrollment or treatment of subjects in 
the study.  
 
10. Monitoring of key safety endpoints (refer to Table 8 in section 2.2.1) will be 
conducted.  
 
 
11. The stopping guidelines serve as a mechanism for consultation with the DSMB for 
additional review, and are not formal “stopping rules” that would mandate 
automatic closure of study enrollment. It is designed to assist the independent 
DSMB in overseeing the study. The DSMB may also request additional interim 
analyses and develop other criteria including provision for monitoring of potential 
late effects to determine when to intervene in the enrollment or treatment of 
subjects in the study.    
 
12. Study accrual and further treatment of subjects will be stopped if multiple (i.e. more 
than 1) subjects develop cardiorespiratory signs and symptoms that are persistent 
or lead to discontinuation of infusion.   
 
8.1.6 Subject observation and discontinuation after IP administration 
The IP administration guidelines in Appendix 1 list the study requirements for subject 
observation and discharge after IP administration. 
8.2 Definition of an Adverse Event 
 
An Adverse Event (AE) is any untoward medical occurrence in a subject or clinical 
investigation subject temporally associated with the use of a medicinal product, whether or 
not considered related to the medicinal product.  The occurrence does not necessarily have 
to have a causal relationship to the treatment received in the study.  An AE can therefore be 
any unfavorable and unintended sign (including an abnormal laboratory finding, for 
example), symptom, or disease (new or exacerbated) temporally associated with the use of 
a medicinal product, whether or not considered related to the medicinal product. 
 
Examples of an AE include: 
- 
Exacerbation of a chronic or intermittent pre-existing condition including either 
an increase in frequency or intensity of the condition. 
 
- 
Significant or unexpected worsening or exacerbation of the condition/indication 
under study. 
 
- 
A new condition detected or diagnosed after study therapy administration even 
though it may have been present prior to the start of the study. 
 

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- 
Pre- or post-treatment events that occur as a result of protocol-mandated 
procedures (e.g., invasive protocol-defined procedures, modification of a 
subject’s previous treatment regimen). 
 
An AE does not include: 
- 
Medical or surgical procedures (e.g., colonoscopy, biopsy).  The medical 
condition that leads to the procedure is an AE. 
 
- 
Social or convenience hospital admissions where an untoward medical 
occurrence did not occur. 
 
- 
Day to day fluctuations of pre-existing disease or conditions present or detected 
at the start of the study that do not worsen. 
 
- 
The disease/disorder being studied or expected progression, signs, or symptoms 
of the disease/disorder being studied unless more severe than expected for the 
subject’s condition. 
 
8.3 Definition of Adverse Reaction 
 
An adverse reaction is any adverse event caused by a drug.  Adverse reactions are a subset 
of all suspected adverse reactions for which there is reason to conclude that the drug 
caused the event. 
 
8.4 
Definition of Suspected Adverse Reaction 
 
Suspected adverse reaction means any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event.  For the purposes of IND safety 
reporting, ‘reasonable possibility’ means there is evidence to suggest a causal relationship 
between the drug and the adverse event.  A suspected adverse reaction implies a lesser 
degree of certainty about causality than adverse reaction, which means any adverse event 
caused by a drug. 
 
8.5 Definition of Serious 
 
An adverse event (AE) or suspected adverse reaction is considered “serious” if it: 
 
1. results in death 
2. is life-threatening (at risk of death at the time of the event) 
3. requires in inpatient hospitalization or prolongation of existing hospitalization 
NOTE:  Complications that occur during hospitalization are AEs.  If a complication 
prolongs hospitalization or fulfills any other serious criteria, the event is serious.  

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Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered to be an AE. 
4. results in disability/incapacity 
NOTE:  The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions.  This definition is not intended to include experiences of 
relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, accidental trauma (i.e., sprained ankle) that may 
interfere or prevent everyday life functions but do not constitute a substantial 
disruption. 
5. is a congenital anomaly/birth defect.   
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in the above definition. 
 
8.6 
Definition of Unexpected 
 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed 
in the investigator brochure or is not listed at the specificity or severity that has been 
observed; or, if an investigator brochure is not required or available, is not consistent with 
the risk information described in the general investigational plan or elsewhere in the 
current application. 
 
8.7 
Clinical Laboratory Assessments and Other Abnormal Assessments as Adverse 
Events and Serious Adverse Events 
 
Abnormal laboratory findings (e.g. clinical chemistry, hematology) or other abnormal 
assessments (e.g., vital signs) that are judged by the Investigator as clinically significant 
will be recorded as AEs or SAEs if they meet the definition of an AE as defined in Section 8.3 
(“Definition of an Adverse Event”) or SAE, as defined in Section 8.6 (“Definition of a Serious 
Adverse Event”).  Clinically significant abnormal laboratory findings or other abnormal 
assessments that are detected during the study or are present at screening and 
significantly worsen following the start of the study will be reported as AEs or SAEs.  
However, clinically significant abnormal laboratory findings or other abnormal 
assessments that are associated with the disease being studied, unless judged by the 
Investigator as more severe than expected for the subject’s condition, or that are present or 
detected at the start of the study but do not worsen, will not be reported as AEs or SAEs. 
 
The Investigator will exercise medical judgment in deciding whether abnormal laboratory 
values are clinically significant. 
 
8.8 Recording of Adverse Events and Serious Adverse Events 
 

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The Investigator should review all documentation (e.g., hospital progress notes, laboratory, 
or diagnostic reports) relative to the event being reported.  The Investigator will then 
record all relevant information regarding an AE/SAE into the electronic data system.  It is 
not acceptable for the Investigator to send photocopies of the subjects’ medical records in 
lieu of completion of the appropriate AE/SAE pages.   
 
The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis should be 
documented as the AE/SAE and not the individual signs and symptoms. 
 
SAEs will be reported to the IRB within 10 working days or within 24 hours if the event is 
life-threatening or results in death. 
 
Pregnancies 
Subject pregnancy must be reported to the Principal Investigator within 1 working day of 
knowledge of the event.  Any subject that becomes pregnant during the study must be 
promptly withdrawn from the study.  Follow-up information regarding the outcome of the 
pregnancy and any postnatal sequelae in the infant will be required.  
8.9 
Intensity of Adverse Events and Serious Adverse Events 
 
The Investigator will make an assessment of intensity for each AE and SAE reported during 
the study.  The assessment will be based on the Investigator’s clinical judgment.  The 
intensity of each AE and SAE should be assigned to one of the following categories: 
Mild:  
 
An event that is easily tolerated by the subject, causing 
 
minimal discomfort and not interfering with everyday 
 
activities. 
Moderate:   
An event that is sufficiently discomforting to interfere with 
 
normal everyday activities. 
Severe:  
 
An event that prevents normal everyday activities. 
Life-threatening:  Immediate risk of death. 
 
An AE that is assessed as severe should not be confused with an SAE.  Severity is a category 
utilized for rating the intensity of an event; and both AEs and SAEs can be assessed as 
severe.  An event is described as ‘serious’ when it meets one of the pre-defined outcomes as 
described in Section 8.6, “Definition of Serious.” 
 
8.10 Causality of Adverse Events and Serious Adverse Events 
 
The Investigator is obligated to assess the causality between study therapy and the 
occurrence of each AE/SAE.  The Investigator will use clinical judgment to determine if 
there is a reasonable possibility that the biological action of the study therapy was 
responsible for AE/SAE being reported.  Alternative causes such as natural history of the 
underlying diseases, concomitant therapy, other risk factors, and the temporal relationship 

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of the event to the study therapy will be considered and investigated.  The Investigator will 
also consult the Clinical Investigator’s Brochure and/or Product Information, for marketed 
products, in the determination of his/her assessment. 
 
The Investigator will use the following questions when assessing causality of an adverse 
event to study therapy.  
 
Is there a reasonable possibility that the study therapy caused the event? Reasonable 
possibility implies that there is evidence that the event was caused by the study product.  
An affirmative answer designates the event as a suspected adverse reaction.  
 
There may be situations when an SAE has occurred and the Investigator has minimal 
information to include in the initial report.  However, it is very important that the 
Investigator always make an assessment of causality. 
 
The relationship between AEs and the study exposure will be classified by the investigator 
as: 
 
- 
None:   
No relationship.  Related to other known etiologies, conditions, or  
 
 
exposures. 
- 
Unlikely:  
Current knowledge suggests that a relationship is unlikely. 
- 
Possible:  
A plausible temporal sequence or response pattern exists but the  
AE may be related to other known etiologies, conditions, or exposures. 
- 
Probable:  
A plausible temporal sequence or response pattern exists and the  
AE cannot be related other known etiologies, conditions, or exposures. 
 
- 
Definite:  
A plausible temporal sequence or response pattern exists and the  
AE can be confirmed by re-challenge or with other supporting data. 
 
8.11 Follow-Up of Adverse Events and Serious Adverse Events 
 
After the initial AE/SAE report, the Investigator is required to proactively follow each 
subject and provide further information on the subject’s condition.  All AEs and SAEs 
documented at a previous visit/contact that are designated as ongoing will be reviewed at 
subsequent visits/contacts.   
 
Adverse events and SAEs will be followed until resolution, until no further changes in the 
event are expected (i.e. the point at which a subject experiencing a critical adverse event is 
treated successfully and stabilized even though they may continue to experience lingering 
sequelae that may never resolve), until the subject is lost to follow-up, or until it is agreed 
that further follow-up of the event is not warranted (e.g. non-serious, study therapy 
unrelated, mild or moderate adverse events ongoing at a subject’s final study visit).  If a 
subject dies during participation in the study or during a recognized follow-up period, the 
Investigator will provide a copy of any post-mortem findings, including histopathology. 
 

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New or updated information will be recorded by modifying the AE forms in the electronic 
data system 
 
8.12 Timeframes for Submitting SAE Reports 
 
Once an Investigator becomes aware that an SAE has occurred in a study subject, he/she 
will record the information in the electronic data record within 48 hours.  Any fatal or life-
threatening event must be reported within 24 hours.  If the Investigator does not have all 
information regarding an SAE, he/she will not wait to receive additional information before 
recording the event in the data system and completing as much information known at the 
time of the submission.  The reporting timeframes for any SAE occurring during the study 
are summarized in Table 12. 
 
TABLE 12 
Serious Adverse Event Reporting Requirements 
 
Initial Reports 
Follow-Up 
Reports 
Type of SAE 
Fatal 
or  
Life-Threatening 
Other SAEs 
Any SAE 
Reporting 
Timeframes 
24 hours 
48 hours 
48 hours 
Documents 
Required 
24 hours: 
Complete as much information 
in the electronic data system 
that is known. 
 
48 hours: 
Fully complete all AE forms  
Fully 
completed AE 
forms 
 
Updated AE 
Forms 
 
 
8.13 Post-Study Adverse Events and Serious Adverse Events 
 
The Investigator should report any death or SAE occurring at any time after a subject has 
completed or terminated a clinical trial, when such death or SAE may reasonably be related 
to the study therapy used in an investigational trial.  Investigators are not obligated to 
actively seek AEs from former study participants. 
8.14 Regulatory Aspects of Adverse Event Reporting 
 
The Investigator will promptly report all SAEs within the timeframes specified in Section 
8.13.  Prompt notification of SAEs by the Investigator is essential so that UMMSM can meet 
legal obligations and fulfill ethical responsibilities towards the safety of all subjects 
participating in UMMSM-sponsored investigational trials. 
 

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The Investigator will comply with the applicable local regulatory requirements related to 
reporting of SAEs to his or her Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC). 
 
This protocol has been filed under an Investigational New Drug (IND) application with the 
FDA.  A given SAE may qualify as an Expedited Safety Report (ESR) if the SAE is both at 
least possibly attributable to study therapy and unexpected.  In this case, all Investigators 
participating in an IND study will receive an ESR.   
 
The ESRs are prepared according to UMMSM policy and are forwarded to the Investigator 
as necessary.  The purpose of the ESR is to fulfill specific regulatory and Good Clinical 
Practice (GCP) requirements regarding the product under investigation.   
Based on previous trials involving intravenous infusion of allogeneic human MSCs, no AEs 
have been attributed to treatment administration; therefore, all AEs will be considered and 
documented as unexpected AEs. 
All AEs occurring at any time during the trial will be collected, documented, and reported 
by the investigator.  For each AE, the investigator will provide the date of onset and 
resolution, intensity, treatment required, outcome, seriousness, and potential causality 
with regards to the study exposure. 
 
9.  
STATISTICAL ANALYSIS 
 
9.1  
Determination of Sample Size and Analysis Population 
 
No formal statistical justification was performed to determine sample size in the Phase I 
study.  Cohort size was determined based on expected requirements for safety analyses 
and projected enrollment rates.  Study participants will be randomized according to a fixed 
allocation permuted block randomization schema.  The allocation ratio will be 1:1:1: and 
the block size will be 4. All enrolled subject who received at least one treatment dose will 
be included in summaries of baseline characteristics, safety, and efficacy.  Reasons for study 
discontinuation will be tabulated. 
 
9.2  
General Statistical Methods 
 
All statistical tests will be performed at an µ=0.05 level of significance, using two-sided 
tests.  Because this is a Phase I study with only exploratory efficacy outcomes, no 
adjustments will be made for multiple analyses.  Continuous variables will be presented by 
descriptive statistics.  Categorical variables will be presented by counts.  Two sided 95% 
confidence intervals will be calculated and presented where appropriate.   
Analysis of AEs will include tabulation by frequency, severity, organ system affected, and 
relationship to study exposure.  Lung function data will be summarized descriptively.  
Subject reported outcome data will be summarized according to the guidelines of each 
questionnaire.    

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9.3 
Interim Analyses 
 
Interim analyses will be conducted at times coincident with regularly scheduled meetings 
of the Data and Safety Monitoring Board (DSMB) at approximately six-month intervals.  
The DSMB Chair will be notified each time an SAE occurs. After all subjects in phase I have 
been followed for 30 days, at that time an independent DSMB will review all available data 
to make an independent recommendation to either keep the specified randomized dose 
1:1:1or to recommend a dose modification for the randomized placebo study.   
 
Policies of the DSMB will be described in the DSMB Charter, which will be prepared by the 
DSMB prior to study initiation. The stopping guidelines serve as a trigger for consultation 
with the DSMB for additional review, and are not formal “stopping rules” that would 
mandate automatic closure of study enrollment. 
 
9.4  
Data Safety Monitoring Board (DSMB) 
9.4.1.  ROLE OF THE DSMB 
This study is designed to test the safety of the study investigational product in subjects 
with chronic inflammation due to metabolic syndrome.  
The purpose of the data safety monitoring board (DSMB) is to advise the investigators 
regarding the continuing safety of study patients and those yet to be recruited to the study, 
as well as the continuing validity and scientific merit of the study.  
This section describes the roles, responsibilities and operating procedures of the DSMB, 
and includes guidelines for communications and interactions between the DSMB and the 
investigators to schedule and format for meetings; format for presentation of data; 
specification of who will have access to interim data and who may attend all or part of 
DSMB meetings; procedures for assessing conflict of interest of potential DSMB members; 
and the method and timing of providing interim reports to the DSMB.  
9.4.2.  Purpose of the DSMB 
The primary function of the DSMB is to review the accumulating unblinded safety data 
from each study group and using the data as the basis for recommendations concerning the 
continuation and/or modification of the study. This will be accomplished through regularly 
scheduled formal meetings and/or additional meetings to review interim summaries of 
safety and efficacy data. The DSMB will make recommendations regarding modification or 
termination of the study in the event of significant study conduct issues or safety concerns. 
The DSMB will not stop the study based on efficacy results favorable to hMSCs, other than 
for all-cause mortality as outlined below. The selected primary and secondary endpoints 
were chosen to measure major morbidity in subjects with chronic inflammation due to 
metabolic syndrome. Given the importance of mortality in patients with metabolic 
syndrome who are at high risk for cardiovascular disease, a stopping boundary based on 
the all-cause mortality rate will be implemented to guide the DSMB.  

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9.4.2.1 DSMB MEMBERSHIP 
The DSMB is an independent, multidisciplinary group consisting of four members 
(inclusive of the DSMB chair). The members include a clinical trialist, a biostatistician, an 
expert gerontologist and an expert cardiologist.  
The DSMB will meet until the study’s database has been locked and a final data review has 
been completed. If a member withdraws from the DSMB, the DSMB chairperson will be 
responsible for selecting an appropriate replacement.  
9.4.2.2 Financial Disclosure and Conflict of Interest 
DSMB membership is restricted to individuals without significant potential or perceived 
conflicts of interest. The source of these conflicts may be financial, scientific, or regulatory 
in nature.  
Members must disclose to the DSMB chairperson their consultancies (direct or indirect) in 
excess of $5,000 or financial interests in any pharmaceutical companies, biotechnology 
companies, or CROs, if these relationships could lead to any conflict of interest or these 
companies’ products involve hMSCs.  
The DSMB chairperson will be responsible for deciding whether consultancies or financial 
interests of the members materially impact their objectivity. This decision is to be based on 
the reasonable belief that their objectivity is not in doubt. DSMB members will be 
responsible for advising the DSMB chairperson of any changes in financial interests in 
pharmaceutical companies, biotechnology companies, including consultancies, during the 
course of their membership. Members of the DSMB who develop significant potential or 
perceived conflicts of interest that may materially impact their objectivity will be asked to 
resign from the DSMB.  
9.4.2.3 DSMB Responsibilities 
The DSMB has the responsibility to:  
1. Review the protocol and all amendments. The DSMB will also be provided the 
Investigator’s Brochure, as it is updated, that includes preclinical and clinical efficacy and 
safety data.  
2. Review the statistical analysis plan with particular attention to the portions describing 
the data to be provided to the DSMB.  
3. Review Periodic Safety Update Reports (PSURs).  
4. Evaluate the conduct of the study including the selection and retention of subjects, extent 
of protocol deviations, treatment adherence, and the quality of the data. The DSMB shall 
make recommendations regarding study conduct as necessary to protect the scientific 

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integrity of the study. The DSMB shall not make recommendations regarding the efficacy 
outcomes or associated analyses.  
5. Review unblinded periodic safety summaries including adverse events, serious adverse 
events, discontinuations, and post-baseline laboratory results. In addition, efficacy and 
mortality data will be reviewed, although the DSMB shall not recommend stopping the 
study for efficacy. 
6. Evaluate the conduct of the study including enrollment rates, the selection and retention 
of patients, protocol deviations, treatment adherence and quality and completeness of the 
data 
7. The DSMB will make recommendations regarding modification or termination of the 
study in the event that significant safety concerns arise during study conduct.  
9.4.2.4 Confidentiality 
The DSMB will be unblinded in its assessment of safety and efficacy data to ensure that the 
DSMB is fully informed in its primary mission of safeguarding the interest of participating 
subjects. The DSMB will have sole access to comparative results of safety data aggregated 
by treatment arm. The DSMB will take all necessary and appropriate steps to safeguard the 
confidentiality of unblinded treatment information it receives to minimize the potential for 
premature conclusions regarding the study results as well as the potential for introducing 
bias into the study.  
9.4.2.5 Study Conduct and Termination 
The DSMB will provide recommendations following review and assessment of the quality 
of study conduct. More specifically, the DSMB will review enrollment rates, consistency in 
complying with eligibility requirements, compliance with the study protocol as well as the 
completeness of the data. In their review of the data, the DSMB will be responsible for 
protecting the safety of the enrolled subjects. If any potential question of safety arises, the 
DSMB will use the efficacy data to assess the possible safety risk in the context of the 
benefit-to-risk profile of study treatment. Based on this information, the DSMB may make 
recommendations to terminate the study if members believe that an undue risk (relative to 
benefit) would be incurred by allowing the study to continue to completion. Otherwise the 
study will be completed to allow investigators to complete the protocol-mandated 
assessments to evaluate the safety of hMSCs in patients with chronic inflammation due to 
metabolic syndrome subjects.  
9.4.2.6 Investigator Responsibilities 
 The investigator has the responsibility to:  
1. Make decisions based on DSMB recommendations in a timely fashion.  

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2. Notify study centers of the outcome of the DSMB meetings, and any DSMB 
recommendations addressing actions to be taken to ensure the integrity of the 
study.  
3. Notify regulatory agencies of DSMB recommendations addressing any emerging 
safety concern not recognized at the start of the study.  
4. Ensure that the unblinded DSMB support team is provided with the data necessary 
for the chosen analyses and reports.  
5. Provide DSMB members with the current protocols and Investigator’s Brochure. 
6. Provide DSMB members with PSURs as published  
7. Attend the open session of each DSMB data review meeting.  
9.4.3  COMMITTEE MEETINGS  
9.4.3.1 Organizational Meeting 
At an organizational meeting the DSMB will discuss the operational aspects of the 
committee. This meeting will include DSMB members and the clinical monitor. The 
documents to be provided before this meeting are:  
1. Study protocol  
2. Preliminary DSMB Statistical Analysis Plan (SAP)  
3. Preliminary list of tables and listings to be provided for interim assessments  
4. Investigator’s Brochure  
5. Food and Drug Administration Guidance: Establishment and Operation of Clinical 
Trial Data Monitoring Committees.  
For all DSMB meetings, a quorum is defined as at least two members of the DSMB in 
addition to the DSMB chairperson.  
9.4.3.2 Review of Periodic Safety Update Reports 
As part of ongoing safety review and obligation to regulatory agencies, safety reports will 
be reported every month. These reports will be available to the DSMB, who shall review 
them in the context of providing additional information to assist the committee’s 
consideration of subject safety. The DSMB members may choose to discuss the PSURs 
during an ad hoc teleconference.  
9.4.3.3 Data Review Meetings 
After all patients enrolled in the Pilot Phase have received the study therapy infusion and 
been followed for 30 days, the DSMB will conduct a full review of all cumulative safety data 
before the trial proceeds to the Randomized Phase.  As part of the cumulative safety data 
review meeting for the pilot phase, the DSMB will recommend that the trial proceed to the 
protocol-specified randomized phase or recommend a dose modification for the 
randomized placebo study. 
Ongoing Monitoring During Randomized Phase 

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Formal data review meetings that include the entire DSMB will be conducted via 
teleconference approximately every three months.  The timeline for the quarterly DSMB 
data review meetings will begin after approximately 25% of patients are enrolled in the 
randomized phase.  Meetings may be postponed due to accrual rates at the DSMB’s 
discretion.  The purpose of the data review is for safety evaluation, and the study may be 
stopped because of significant safety concerns.  SAEs which are related to stopping rules 
will be continuously evaluated and the full DSMB will be informed of any extra risk. The 
DSMB will evaluate all safety data available for each patient as appropriate. 
Open session 
Blinded data will be provided to the DSMB approximately 1 week before each data review 
meeting. The report will contain:  
1. Protocol status including any protocol changes  
2. Data sources and cutoff dates  
3. Analysis methods applied specifically to the open session report  
4. Subject enrollment by month  
5. Protocol deviations  
6. Early treatment discontinuations and study withdrawals  
7. Demographic and baseline characteristics  
8. Duration of follow-up at time of data cutoff  
 
 Closed Session  
Only the DSMB members will participate in closed sessions. Unblinded data will be 
presented to the DSMB in closed session and discussed by the DSMB. "Unblinded" means 
that the name of actual treatment arm is associated with individual subject data listings 
and summaries of data. At the chairperson’s discretion, the DSMB may discuss or vote on 
potential study conduct recommendations at closed session. 
The closed session report will contain data separated and identified by treatment group. 
This report (hard copy) will be provided to the DSMB approximately 1 week before each 
data review meeting and will include:  
1. Data sources and cutoff dates  
2. Analysis methods applied specifically to the closed session report  
3. Subject enrollment  
4. Protocol deviations  
5. Early treatment discontinuations and study withdrawals  
6. Demographic and baseline characteristics  
7. Primary and secondary efficacy outcome measures 
8. Prohibited concomitant medications  
9. Adverse events 
10. Serious adverse events  

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Following the closed session, the DSMB chairperson will issue, within 24 hours, one of the 
following recommendations as determined by the DSMB:  
1. Continue the study, with or without modifications.  
2. Terminate the study for safety concerns.  
Separate meeting minutes for the open and closed sessions will be prepared by the DSMB 
project manager, then reviewed and issued by the DSMB chairperson. The DSMB support 
team will maintain copies of the meeting minutes for both the open and closed meetings. 
To preserve the integrity of the study, the detailed rationale and discussion of comparative 
unblinded data will be included only in the closed meeting minutes 
 
 Follow-Up Open Session  
Immediately following the closed session, the DSMB will meet with the investigators to 
discuss any study conduct concerns. This follow-up open session may be attended by DSMB 
Members, clinical monitor, and study staff. Potential recommendations from the DSMB 
regarding study discontinuation or continuation, with or without modification, will not be 
communicated in this open session. 
 
 Closed Executive Session  
At the discretion of the DSMB chairperson, a closed executive session may be held. Closed 
executive sessions will include only DSMB members. Discussion of unblinded study data 
and potential DSMB recommendations and voting may take place in closed executive 
session. The DSMB may choose whether to write minutes of the closed executive sessions.  
9.4.4  DATA FLOW 
9.4.4.1 Communications and Reports 
For each DSMB meeting, the open session and closed session reports will be prepared by 
the DSMB support team. Open session reports will be circulated to all attendees of the open 
session. The closed session reports will be circulated to DSMB members only. The closed 
session reports will be retrieved from the DSMB members by the DSMB support team and 
destroyed after the closed session. The DSMB support team will maintain copies of all 
reports from the open and closed sessions.  
9.4.4.2 Review of Unblinding Requests 
Except as required by regulatory authorities for safety reporting, individual subjects’ 
treatment assignments will not be unblinded during the conduct of the study, unless a 
subject safety issue arises in which unblinding is necessary to ensure optimal subject 
management. It is not anticipated that unblinding will be necessary, given the hMSCs can be 
safely discontinued at any time a safety concern arises. The DSMB will be informed in a 
timely manner of any case for which unblinding was requested and performed.  

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9.4.4.3 DSMB Additional Analysis Requests  
The DSMB may request additional analyses from the statistician if deemed necessary to 
fulfill the mission of the DSMB. If based on the additional data the DSMB feels there is a 
need for an unscheduled formal meeting, the DSMB chairperson will arrange. 
9.4.4.4 Confidentiality  
All documents will be held in strict confidence by the DSMB, and all documents provided to 
the DSMB will be collected and destroyed at the end of all DSMB meetings by the DSMB 
support team.  
9.4.5  COMMUNICATION 
 
9.4.5.1 DSMB Minutes 
The DSMB chairperson is responsible for issuing minutes of the open and closed sessions. 
Minutes of the open session will be distributed to all open meeting attendees within two 
weeks of the meeting. Minutes of the closed session will be distributed to the members of 
the DSMB within two weeks of the meeting. At the conclusion of the study, the DSMB 
support team will send a complete set of the open and closed reports, minutes of the open 
and closed sessions with the tables and listings, all presentations and copies of the 
recommendation forms to the investigators.  
9.4.5.2 DSMB Recommendations 
If the DSMB recommends modification to, or termination of, the study, the chairperson of 
the DSMB will contact the investigators within 24 hours of making the decision.  
Recommendations for modifications other than termination should be accompanied by the 
rationale for the recommendation and the minimum amount of data required to make a 
decision. The investigator will be responsible for promptly reviewing the DSMB 
recommendations and determining whether amendments to the protocol or changes 
regarding the study conduct are required and if reporting to regulatory authorities is 
warranted (FDA, 2006).  
Should there be disagreement between the DSMB and the investigators around the decision 
to stop or modify the study a separate compliance committee will be appointed. This 
committee is comprised of individuals who have extensive experience in the 
pharmaceutical industry and a deep appreciation of the ethical issues surrounding the 
conduct of clinical studies and are responsible for the investigator’s code of ethics. The 
Compliance Committee is charged with independently evaluating differing opinions that 
may arise between the investigator and DSMB and applying the highest ethical standards 
with respect to determining the best interests of subjects enrolled in the study.  
 

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10.  
STUDY ADMINISTRATION 
10.1 Regulatory Authority Approval 
 
This study will be conducted in accordance with Good Clinical Practice (GCP) requirements 
described in the current revision of International Conference on Harmonization of 
Technical Requirements of Pharmaceuticals for Human Use (ICH) Guidelines and all 
applicable regulations, including current United States Code of Federal Regulations (CFR), 
Title 21, Parts 11, 50, 54, 56, and 312 and Title 45, Part 164.  Compliance with these 
regulations and guidelines also constitutes compliance with the ethical principles 
described in the current revision of the Declaration of Helsinki.  This study will also be 
carried out in accordance with local legal requirements. 
 
 
10.2  Ethics Approval 
 
It is the Investigator’s responsibility to ensure that prior to initiating this study; this 
protocol is reviewed and approved by the appropriate local IRB.  The composition and 
conduct of this committee must conform to the United States CFR.   
The IRB/IEC must also review and approve the site’s informed consent form (ICF), other 
written information provided to the subject and all advertisements that may be used for 
subject recruitment.   
If it is necessary to amend the protocol or the ICF during the study, the Investigator will be 
responsible for ensuring that the IRB/IEC reviews and approves these amended 
documents. An IRB/IEC approval of the amended protocol and/or ICF must be obtained in 
writing before implementation of the amended procedures and before new subjects are 
consented to participate in the study using the amended version of the ICF. 
 
10.3  Subject Informed Consent 
 
Before being admitted to the clinical study, all subjects must consent in writing to 
participate.  An ICF will be given to each subject, which will contain all United States 
federally required elements, all ICH-required elements, and Health Insurance Portability 
and Accountability Act Authorization (HIPAA) information in language that is 
understandable to the subject.  
 
The process of obtaining the informed consent will be in compliance with all federal 
regulations, ICH requirements, and local laws.   
The investigator or designee will review the study with each subject.  The review will 
include the nature, scope, procedures, and possible consequences of the subject's 
participation in the study.  The ICF and review must be in a form understandable to the 
subject.  The Investigator or designee and the subject must both sign and date the ICF after 
review and before the subject can participate in the study.  The subject will receive a copy 
of the signed and dated form, and the original will be retained in the site study files.  The 

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Investigator or his/her designee must emphasize to the subject that study participation is 
entirely voluntary and that consent regarding study participation may be withdrawn at any 
time without penalty or loss of benefits to which the subject is otherwise entitled. 
If the ICF is amended during the study, the Investigator must follow all applicable 
regulatory requirements pertaining to approval of the amended ICF by the IRB/IEC.  The 
site must use the amended consent form for all new subjects and repeat the consent 
process with the amended ICF for any ongoing subjects. 
If a subject is unable to come to site due to COVID-19 the following methods will be used to 
obtain informed consent that meets the requirements of local regulations, ICH guidelines, 
and the IRB/EC or study center, where applicable:  
• Obtain the informed consent electronically; OR  
• Obtain the informed consent by teleconference/video conference in alignment with 
local regulatory guidance.  
How the consent was obtained and reason why it was obtained using that particular 
method should be documented in the eCRF. The signature may be obtained via a secure 
email or digital signature. If it is not possible to obtain a digital image of the signed page, a 
statement of consent can be obtained via cellphone text message or via secure email. This 
does not preclude a site from obtaining consent via paper, if such arrangements can be 
made, e.g. fax, mail. 
 
10.4  
Confidentiality of Information 
 
Subjects’ names will remain confidential and will not be included in the database.  Only 
subject number, subject initials, and birth date will be recorded in the data system.  If the 
subject name appears on any other document collected (e.g., hospital discharge summary), 
the name must be deleted before the document is transmitted.  All study findings will be 
stored in electronic databases.  The subjects will give explicit permission for 
representatives of regulatory authorities and the IRB/IEC to inspect their medical records 
to verify the information collected.   
 
Subjects will be informed that all personal information made available for inspection will 
be handled in the strictest confidence and in accordance with all state, local, and federal 
data protection/privacy laws, including, without limitation, the HIPAA. 
Participants will be asked to voluntarily provide written authorization prior to requesting 
or disclosing private health information either as part of the written ICF or as a separate 
authorization form. The authorization will contain all required elements specified by 45 
CFR 164, and will allow the site to access study-related private health information until the 
conclusion of the clinical study.  The authorization will remain valid and in full force and 
effect until the first to occur of (1) the expiration of two years after the study therapy is 
approved for the indication being studied, or (2) the expiration of two years after the 
research program is discontinued.  Individual subject medical information obtained during 
this study is confidential and its disclosure to third parties (other than those mentioned in 
this Section) is strictly prohibited.  In addition, medical information obtained during this 

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study may be provided to the subject's personal physician or to other appropriate medical 
personnel when required in connection with the subject's continued health and welfare. 
The investigator will maintain a personal subject identification list (subject and treatment 
numbers with the corresponding subject names) to enable records to be identified.   
10.5  
Payments to Subjects 
 
Subjects will be reimbursed $25 at the end of each follow-up visit (Week 2 – Month 12) for 
a total remuneration of $125.  These disbursements are meant to cover the time required 
to complete these study visits and all necessary travel and parking expenses.  
 
10.6         Payments to Donors 
Normal donors for generation of allo-MSC will be reimbursed $500 at the end of BM 
aspiration. This payment will compensate donors for lost time, parking, and travel 
expenses.  

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APPENDIX 1:  
Infusion Guidelines 
 
Prior to the start of the infusion the following procedures and assessments will be 
conducted on the study subject: 
1. 
Vital Signs: Blood pressure, heart rate, respiratory rate, and temperature, will 
be measured within 15 minutes prior to the initiation of the infusion. 
2. 
Oxygen saturation will be continuously monitored by pulse oximetry for at 
least 30 minutes prior to initiation of IP infusion. 
3. 
Confirm that IV access is established and that the IV catheter is no smaller 
than 20 gauge 
4. 
Study personnel needs to verify that the following pre-medications have 
been administered 30 minutes to an hour prior to infusion, unless otherwise 
determined by the physician: 
 
▪ Hydrocortisone 25 – 50 mg IV 
▪ Diphenhydramine (Benadryl) 25 – 50 mg IV 
 
Note: No other medications should be given during the infusion unless 
determined medically necessary by the Investigator. 
 
5. 
Document pre-medications given prior to infusion on the source documents 
6. 
Required IV Infusion materials as follows: 
▪ 0.9 % normal saline IV infusion bag 
▪ IV Pump tubing 
▪ IV extension tubing (unless using a central line) 
▪ Volumetric infusion pump 
▪ Gloves 
7. 
Remove 0.9% normal saline infusion bag and connect IV tubing to the 
volumetric infusion pump 
8. 
Cover the IV tubing with the blinding material provided with the infusion bag 
by the drug preparation technician.  
 
During the IP infusion the following procedures and assessments will be conducted on the 
study subject: 
 
1. 
Monitor the subject continuously with pulse oximetry 
2. 
Hang the blinded infusion bag. Investigational product (IP) should   not be 
“piggybacked” through another line 
3. 
Intravenously administer the IP at a rate of 2ml/min.  
 
Note: Study personnel administering the IP must be present throughout  
 
the infusion process. The Investigator must be available at the site  
 
 
during the infusion process in case an emergency should arise.  
4. 
Record the start time of the infusion bag  

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5. 
Gently squeeze the infusion bag several times every 15 minutes to assure 
uniform dispersion of contents 
6. 
Vital signs and O2 saturation will be measured every 15 minutes until the end 
of IP infusion 
7. 
Record the total volume infused from the IP bag 
8. 
At the end of the IP infusion, close the line and flush 25ml of 0.9% normal 
saline into the luer lock connector on the bottom of the IP bag, reopen line 
and allow to infuse at a rate of 2mL/min until completion. 
9. 
Discard IV tubing according to established guidelines 
 
Procedures post-infusion: 
1. 
Vital signs will be monitored at 15 minutes, 30 minutes, 1 hour, and 2 
hours post IP infusion 
2. 
The subject will be monitored for a minimum of 2 hours post IP 
infusion with continuous pulse oximetry 
3. 
If the O2 saturation decreases to < 90% over a continual period of 3 – 5 
minutes, then supplemental oxygen may be added or increased during the 
two hours post-infusion observation period.  
4. 
If at the end of the 2-hour observation period, if a subject’s O2 
saturation stays below 90% then the subject will be provided additional 
oxygen to maintain a saturation of >90% at room air up to 4 hours post 
infusion.  
5. 
After the minimum two-hour observation period, the subject will be 
continuously monitored and discharged the following day, if no complaints 
are experienced, such as shortness of breath or other objective signs of 
cardiorespiratory compromise.  
6. 
Subjects not meeting criteria for discharge will be assessed by the 
Investigator 
during 
the 
observation 
period 
to 
further 
determine 
hospitalization otherwise not specified in the protocol. 
 
Subject Stopping Guidelines: 
 
1. Any subject who develops persistent (that is, still existing more than 3 hours after 
the end of IP infusion) cardiorespiratory signs or symptoms including hypoxemia 
(defined per oxygenation criteria of 93% on room air at rest, or shortness of breath, 
tachypnea, tachycardia, hypotension, or palpitations) will continue with all 
scheduled follow-up if such follow-up is considered safe in the opinion of the 
Investigator. The infusion will be stopped if the oxygen saturation does not return to 
>93% within 3 minutes of initiating supplemental oxygen or if the subject requires 
greater than 2L/min supplemental oxygen to achieve the required saturation of 
>93%.  If a subject requires the addition of oxygen, it will be continued for 4 hours 
after the completion of the infusion.  At that time, oxygen will be weaned off to 
maintain a saturation >93% on room air. 
 

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2. Any subject whose infusion is stopped due to cardiorespiratory distress will receive 
no further IP infusions but will continue with all scheduled follow-up if such follow-
up is considered safe in the opinion of the Investigator. 
 
3. Any subject who develops any sign or symptom that, at the discretion of the 
Investigator, warrants the discontinuation of infusion will receive no further IP 
infusions but will continue with all scheduled follow-up if such follow-up is 
considered safe in the opinion of the Investigator. 
 
4. Infusion of the IP may be stopped if there is an adverse event that the Investigator 
believes is related to the IP or if there is an issue with the IP infusion. 

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APPENDIX 2: Dobutamine Stress Echo (DSE) Instructions 
 
A Dobutamine Stress Echocardiogram will be performed at screening and at the Month 6 
follow-up visit. Dobutamine is a chemical, which can assist in mimicking the effect of 
exercise on subjects in order to assess the heart muscle and ejection fraction when under 
stress. 
Procedure Details: 
- 
Obtain baseline heart rate, blood pressure, Electrocardiogram (ECG), physical exam, 
and echocardiographic images on the study participant.  
- 
Place an Intravenous (IV) line to administer Dobutamine. 
- 
Administer progressively increasing doses of Dobutamine (5, 10, 20, and 30 
mcg/kg/min) in 3-minute intervals 
- 
Obtain Heart rate, Blood Pressure, ECG, and echocardiographic images at each 
dosage. 
- 
After completing measurements at 30mcg/kg/min dosage, discontinue Dobutamine 
and allow heart rate to recover to baseline and obtain repeat echocardiographic 
images. 
 
Required Data Points: 
1. Right Ventricular end-diastolic dimension (RVDd) 
2. Interventricular Septal end-diastolic dimension (IVSd) 
3. Left Ventricular Internal end-diastolic dimension (LVIDd) 
4. Left Ventricular Internal end-systolic dimension (LVIDs) 
5. Left Ventricular Posterior Wall end-diastolic dimension (LVPWd) 
6. End-Diastolic Volume (EDV) 
7. End-Systolic Volume (ESV) 
8. Left Atrial (LA) dimension 
9. Peak infusion rate 
10. Peak heart rate  
11. Peak blood pressure (systolic/diastolic) 
12. Resting biplane ejection fraction 
13. Ejection fraction at 5 mcg/kg/min 
14. Ejection fraction at 10 mcg/kg/min 
15. Ejection fraction at 20 mcg/kg/min 
16. Ejection fraction at 30 mcg/kg/min 
17. Evidence of Mitral Valve Regurgitation (MR) 
18. Evidence of Pericardial Effusion (PE) 

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APPENDIX 3: Flow Mediated Diameter percent change (FMD%) Instructions  
A Flow Mediated Diameter percent change will be performed three times during the study, 
once at screening, baseline, and at the Month 3 follow-up visit. This exam will assess 
vascular function.  
Procedure Details: 
- 
All measurements of the brachial artery diameter and FMD will be performed in the 
morning, in a quiet and dark room and at controlled ambient temperature. 
- 
Studies will be conducted after an overnight fast of at least 10 hours (water is 
permitted), with the subjects supine and after 10 minutes of rest.  
- 
The subject's right arm will be comfortably immobilized in an extending position, 
allowing for ultrasound scanning of the brachial artery 5–10 cm above the 
antecubital fossa.  
- 
Blood flow is manipulated in the brachial artery by a pneumatic cuff placed around 
the forearm distal to the segment of artery being imaged inflated to a suprasystolic 
pressure (240 mm Hg) for 5 min and released, resulting in a brief episode of reactive 
hyperemia. Changes in brachial artery diameter in response to the increase in blood 
flow once the forearm cuff is deflated are recorded.   
- 
Recovery of brachial artery diameter is assessed for an additional 5 min.  Images are 
all digitized and stored on portable storage device following recording for later off-
line scoring.  
- 
Two repeated tests are performed. An inter-test rest period of 5 min is used and the 
second test is not conducted until mean arterial pressure is within 5 mmHg of the 
initial resting mean arterial pressure taken following the initial rest period. 
- 
Recordings are digitized continuously for 5 min of baseline recording, 5 min of cuff 
inflation to supra-systolic pressure, and for 5 min after cuff deflation when brachial 
flow increases to accommodate the dilated resistance vessels.  
FMD% more than 10% is considered a normal response. Lower than 10% FMD% reflects 
endothelial dysfunction, which means a high likelihood to develop cardiovascular event in 
the future. Subjects with negative FMD% results (the artery is constricted after stress and 
not dilated as was expected) have the worst prognosis. 

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References 
 
 (1)  Kaur, J. A Comprehensive Review on Metabolic Syndrome. Cardiol. Res. Pract. 2014, 
2014, 943162. 
 (2)  Thande, N.; Rosenson, R. S. Vascular Biomarkers in the Metabolic Syndrome. Expert. 
Rev. Mol. Diagn. 2009, 9, 209-215. 
 (3)  Alberti, K. G.; Eckel, R. H.; Grundy, S. M.; Zimmet, P. Z.; Cleeman, J. I.; Donato, K. A.; 
Fruchart, J. C.; James, W. P.; Loria, C. M.; Smith, S. C., Jr. Harmonizing the Metabolic 
Syndrome: a Joint Interim Statement of the International Diabetes Federation Task 
Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; 
American Heart Association; World Heart Federation; International Atherosclerosis 
Society; and International Association for the Study of Obesity. Circulation 2009, 
120, 1640-1645. 
 (4)  Silva, V.; Stanton, K. R.; Grande, A. J. Harmonizing the Diagnosis of Metabolic 
Syndrome--Focusing on Abdominal Obesity. Metab Syndr. Relat Disord. 2013, 11, 
102-108. 
 (5)  Alberti, K. G.; Zimmet, P.; Shaw, J. The Metabolic Syndrome--a New Worldwide 
Definition. Lancet 2005, 366, 1059-1062. 
 (6)  Olijhoek, J. K.; van der Graaf, Y.; Banga, J. D.; Algra, A.; Rabelink, T. J.; Visseren, F. L. 
The Metabolic Syndrome Is Associated With Advanced Vascular Damage in Patients 
With Coronary Heart Disease, Stroke, Peripheral Arterial Disease or Abdominal 
Aortic Aneurysm. Eur. Heart J. 2004, 25, 342-348. 
 (7)  Ford, E. S. Prevalence of the Metabolic Syndrome Defined by the International 
Diabetes Federation Among Adults in the U.S. Diabetes Care 2005, 28, 2745-2749. 
 (8)  Vykoukal, D.; Davies, M. G. Vascular Biology of Metabolic Syndrome. J. Vasc. Surg. 
2011, 54, 819-831. 
 (9)  Szasz, T.; Bomfim, G. F.; Webb, R. C. The Influence of Perivascular Adipose Tissue on 
Vascular Homeostasis. Vasc. Health Risk Manag. 2013, 9, 105-116. 
 (10)  Kim, J. A.; Montagnani, M.; Koh, K. K.; Quon, M. J. Reciprocal Relationships Between 
Insulin Resistance and Endothelial Dysfunction: Molecular and Pathophysiological 
Mechanisms. Circulation 2006, 113, 1888-1904. 
 (11)  Rajala, M. W.; Scherer, P. E. Minireview: The Adipocyte--at the Crossroads of Energy 
Homeostasis, Inflammation, and Atherosclerosis. Endocrinology 2003, 144, 3765-
3773. 

The CERES Trial  
 
Page 90 
  Oct 22, 2020 
ISCI / University of Miami Miller School of Medicine 
   **CONFIDENTIAL AND PROPRIETARY** 
 
 (12)  Taskinen, M.; Saarinen-Pihkala, U. M.; Hovi, L.; Lipsanen-Nyman, M. Impaired 
Glucose Tolerance and Dyslipidaemia As Late Effects After Bone-Marrow 
Transplantation in Childhood. Lancet 2000, 356, 993-997. 
 (13)  Cubbon, R. M.; Kahn, M. B.; Wheatcroft, S. B. Effects of Insulin Resistance on 
Endothelial Progenitor Cells and Vascular Repair. Clin. Sci. (Lond) 2009, 117, 173-
190. 
 (14)  Chalouhi, N.; Ali, M. S.; Jabbour, P. M.; Tjoumakaris, S. I.; Gonzalez, L. F.; Rosenwasser, 
R. H.; Koch, W. J.; Dumont, A. S. Biology of Intracranial Aneurysms: Role of 
Inflammation. J. Cereb. Blood Flow Metab 2012, 32, 1659-1676. 
 (15)  Hill, J. M.; Zalos, G.; Halcox, J. P.; Schenke, W. H.; Waclawiw, M. A.; Quyyumi, A. A.; 
Finkel, T. Circulating Endothelial Progenitor Cells, Vascular Function, and 
Cardiovascular Risk. N. Engl. J. Med. 2003, 348, 593-600. 
 (16)  Rajendran, P.; Rengarajan, T.; Thangavel, J.; Nishigaki, Y.; Sakthisekaran, D.; Sethi, G.; 
Nishigaki, I. The Vascular Endothelium and Human Diseases. Int. J. Biol. Sci. 2013, 9, 
1057-1069. 
 (17)  Vanhoutte, P. M.; Shimokawa, H.; Tang, E. H.; Feletou, M. Endothelial Dysfunction 
and Vascular Disease. Acta Physiol (Oxf) 2009, 196, 193-222. 
 (18)  Gutierrez, E.; Flammer, A. J.; Lerman, L. O.; Elizaga, J.; Lerman, A.; Fernandez-Aviles, 
F. Endothelial Dysfunction Over the Course of Coronary Artery Disease. Eur. Heart J. 
2013, 34, 3175-3181. 
 (19)  Matsue, Y.; Suzuki, M.; Nagahori, W.; Ohno, M.; Matsumura, A.; Hashimoto, Y.; 
Yoshida, K.; Yoshida, M. Endothelial Dysfunction Measured by Peripheral Arterial 
Tonometry Predicts Prognosis in Patients With Heart Failure With Preserved 
Ejection Fraction. Int. J. Cardiol. 2013, 168, 36-40. 
 (20)  Duncan, E. R.; Walker, S. J.; Ezzat, V. A.; Wheatcroft, S. B.; Li, J. M.; Shah, A. M.; 
Kearney, M. T. Accelerated Endothelial Dysfunction in Mild Prediabetic Insulin 
Resistance: the Early Role of Reactive Oxygen Species. Am. J. Physiol Endocrinol. 
Metab 2007, 293, E1311-E1319. 
 (21)  Wheatcroft, S. B.; Shah, A. M.; Li, J. M.; Duncan, E.; Noronha, B. T.; Crossey, P. A.; 
Kearney, M. T. Preserved Glucoregulation but Attenuation of the Vascular Actions of 
Insulin in Mice Heterozygous for Knockout of the Insulin Receptor. Diabetes 2004, 
53, 2645-2652. 
 (22)  Eren, E.; Yilmaz, N.; Aydin, O. Functionally Defective High-Density Lipoprotein and 
Paraoxonase: a Couple for Endothelial Dysfunction in Atherosclerosis. Cholesterol. 
2013, 2013, 792090. 
 (23)  Fadini, G. P.; Miorin, M.; Facco, M.; Bonamico, S.; Baesso, I.; Grego, F.; Menegolo, M.; 
de Kreutzenberg, S. V.; Tiengo, A.; Agostini, C.; Avogaro, A. Circulating Endothelial 

The CERES Trial  
 
Page 91 
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   **CONFIDENTIAL AND PROPRIETARY** 
 
Progenitor Cells Are Reduced in Peripheral Vascular Complications of Type 2 
Diabetes Mellitus. J. Am. Coll. Cardiol. 2005, 45, 1449-1457. 
 (24)  Jialal, I.; Devaraj, S.; Singh, U.; Huet, B. A. Decreased Number and Impaired 
Functionality of Endothelial Progenitor Cells in Subjects With Metabolic Syndrome: 
Implications for Increased Cardiovascular Risk. Atherosclerosis 2010, 211, 297-302. 
 (25)  Tousoulis, D.; Andreou, I.; Antoniades, C.; Tentolouris, C.; Stefanadis, C. Role of 
Inflammation and Oxidative Stress in Endothelial Progenitor Cell Function and 
Mobilization: Therapeutic Implications for Cardiovascular Diseases. Atherosclerosis 
2008, 201, 236-247. 
 (26)  Watson, T.; Goon, P. K.; Lip, G. Y. Endothelial Progenitor Cells, Endothelial 
Dysfunction, Inflammation, and Oxidative Stress in Hypertension. Antioxid. Redox. 
Signal. 2008, 10, 1079-1088. 
 (27)  Westerweel, P. E.; Visseren, F. L.; Hajer, G. R.; Olijhoek, J. K.; Hoefer, I. E.; de, B. P.; 
Rafii, S.; Doevendans, P. A.; Verhaar, M. C. Endothelial Progenitor Cell Levels in 
Obese Men With the Metabolic Syndrome and the Effect of Simvastatin Monotherapy 
Vs. Simvastatin/Ezetimibe Combination Therapy. Eur. Heart J. 2008, 29, 2808-2817. 
 (28)  Bartholomew, A.; Sturgeon, C.; Siatskas, M.; Ferrer, K.; McIntosh, K.; Patil, S.; Hardy, 
W.; Devine, S.; Ucker, D.; Deans, R.; Moseley, A.; Hoffman, R. Mesenchymal Stem Cells 
Suppress Lymphocyte Proliferation in Vitro and Prolong Skin Graft Survival in Vivo. 
Exp. Hematol. 2002, 30, 42-48. 
 (29)  Djouad, F.; Plence, P.; Bony, C.; Tropel, P.; Apparailly, F.; Sany, J.; Noel, D.; Jorgensen, 
C. Immunosuppressive Effect of Mesenchymal Stem Cells Favors Tumor Growth in 
Allogeneic Animals. Blood 2003, 102, 3837-3844. 
 (30)  Krampera, M.; Glennie, S.; Dyson, J.; Scott, D.; Laylor, R.; Simpson, E.; Dazzi, F. Bone 
Marrow Mesenchymal Stem Cells Inhibit the Response of Naive and Memory 
Antigen-Specific T Cells to Their Cognate Peptide. Blood 2003, 101, 3722-3729. 
 (31)  Le, B. K.; Tammik, L.; Sundberg, B.; Haynesworth, S. E.; Ringden, O. Mesenchymal 
Stem Cells Inhibit and Stimulate Mixed Lymphocyte Cultures and Mitogenic 
Responses Independently of the Major Histocompatibility Complex. Scand. J. 
Immunol. 2003, 57, 11-20. 
 (32)  Potian, J. A.; Aviv, H.; Ponzio, N. M.; Harrison, J. S.; Rameshwar, P. Veto-Like Activity 
of Mesenchymal Stem Cells: Functional Discrimination Between Cellular Responses 
to Alloantigens and Recall Antigens. J. Immunol. 2003, 171, 3426-3434. 
 (33)  Tse, W. T.; Pendleton, J. D.; Beyer, W. M.; Egalka, M. C.; Guinan, E. C. Suppression of 
Allogeneic T-Cell Proliferation by Human Marrow Stromal Cells: Implications in 
Transplantation. Transplantation 2003, 75, 389-397. 

The CERES Trial  
 
Page 92 
  Oct 22, 2020 
ISCI / University of Miami Miller School of Medicine 
   **CONFIDENTIAL AND PROPRIETARY** 
 
 (34)  Barbieri, M.; Ferrucci, L.; Ragno, E.; Corsi, A.; Bandinelli, S.; Bonafe, M.; Olivieri, F.; 
Giovagnetti, S.; Franceschi, C.; Guralnik, J. M.; Paolisso, G. Chronic Inflammation and 
the Effect of IGF-I on Muscle Strength and Power in Older Persons. Am. J. Physiol 
Endocrinol. Metab 2003, 284, E481-E487. 
 (35)  Cesari, M.; Penninx, B. W.; Pahor, M.; Lauretani, F.; Corsi, A. M.; Rhys, W. G.; Guralnik, 
J. M.; Ferrucci, L. Inflammatory Markers and Physical Performance in Older Persons: 
the InCHIANTI Study. J. Gerontol. A Biol. Sci. Med. Sci. 2004, 59, 242-248. 
 (36)  Ganesh, B. B.; Bhattacharya, P.; Gopisetty, A.; Prabhakar, B. S. Role of Cytokines in 
the Pathogenesis and Suppression of Thyroid Autoimmunity 3. J. Interferon Cytokine 
Res. 2011, 31, 721-731. 
 (37)  Weis, M.; Wildhirt, S. M.; Schulze, C.; Pehlivanli, S.; Fraunberger, P.; Meiser, B. M.; 
von, S. W. Modulation of Coronary Vasomotor Tone by Cytokines in Cardiac 
Transplant Recipients. Transplantation 1999, 68, 1263-1267. 
 (38)  Xing, L.; Jiang, M.; Dong, L.; Gao, J.; Hou, Y.; Bai, G.; Luo, G. Cardioprotective Effects of 
the YiQiFuMai Injection and Isolated Compounds on Attenuating Chronic Heart 
Failure Via NF-KappaB Inactivation and Cytokine Suppression17. J. Ethnopharmacol. 
2013, 148, 239-245. 
 (39)  Abbatecola, A. M.; Ferrucci, L.; Grella, R.; Bandinelli, S.; Bonafe, M.; Barbieri, M.; Corsi, 
A. M.; Lauretani, F.; Franceschi, C.; Paolisso, G. Diverse Effect of Inflammatory 
Markers on Insulin Resistance and Insulin-Resistance Syndrome in the Elderly. J. 
Am. Geriatr. Soc. 2004, 52, 399-404. 
 (40)  Licastro, F.; Grimaldi, L. M.; Bonafe, M.; Martina, C.; Olivieri, F.; Cavallone, L.; 
Giovanietti, S.; Masliah, E.; Franceschi, C. Interleukin-6 Gene Alleles Affect the Risk of 
Alzheimer's Disease and Levels of the Cytokine in Blood and Brain. Neurobiol. Aging 
2003, 24, 921-926. 
 (41)  Giovannini, S.; Onder, G.; Liperoti, R.; Russo, A.; Carter, C.; Capoluongo, E.; Pahor, M.; 
Bernabei, R.; Landi, F. Interleukin-6, C-Reactive Protein, and Tumor Necrosis Factor-
Alpha As Predictors of Mortality in Frail, Community-Living Elderly Individuals. J. 
Am. Geriatr. Soc. 2011, 59, 1679-1685. 
 (42)  Leng, S. X.; Xue, Q. L.; Tian, J.; Walston, J. D.; Fried, L. P. Inflammation and Frailty in 
Older Women. J. Am. Geriatr. Soc. 2007, 55, 864-871. 
 (43)  Walston, J.; McBurnie, M. A.; Newman, A.; Tracy, R. P.; Kop, W. J.; Hirsch, C. H.; 
Gottdiener, J.; Fried, L. P. Frailty and Activation of the Inflammation and Coagulation 
Systems With and Without Clinical Comorbidities: Results From the Cardiovascular 
Health Study. Arch. Intern. Med. 2002, 162, 2333-2341. 
 (44)  Hubbard, R. E.; O'Mahony, M. S.; Savva, G. M.; Calver, B. L.; Woodhouse, K. W. 
Inflammation and Frailty Measures in Older People. J. Cell Mol. Med. 2009, 13, 3103-
3109. 

The CERES Trial  
 
Page 93 
  Oct 22, 2020 
ISCI / University of Miami Miller School of Medicine 
   **CONFIDENTIAL AND PROPRIETARY** 
 
 (45)  Serviddio, G.; Romano, A. D.; Greco, A.; Rollo, T.; Bellanti, F.; Altomare, E.; 
Vendemiale, G. Frailty Syndrome Is Associated With Altered Circulating Redox 
Balance and Increased Markers of Oxidative Stress. Int. J. Immunopathol. Pharmacol. 
2009, 22, 819-827. 
 (46)  Cesari, M.; Penninx, B. W.; Newman, A. B.; Kritchevsky, S. B.; Nicklas, B. J.; Sutton-
Tyrrell, K.; Rubin, S. M.; Ding, J.; Simonsick, E. M.; Harris, T. B.; Pahor, M. 
Inflammatory Markers and Onset of Cardiovascular Events: Results From the Health 
ABC Study. Circulation 2003, 108, 2317-2322. 
 (47)  Fried, L. P.; Ferrucci, L.; Darer, J.; Williamson, J. D.; Anderson, G. Untangling the 
Concepts of Disability, Frailty, and Comorbidity: Implications for Improved 
Targeting and Care. J. Gerontol. A Biol. Sci. Med. Sci. 2004, 59, 255-263. 
 (48)  Schulman, I. H.; Hare, J. M. Key Developments in Stem Cell Therapy in Cardiology. 
Regen. Med. 2012, 7, 17-24. 
 (49)  Schmidt-Lucke, C.; Rossig, L.; Fichtlscherer, S.; Vasa, M.; Britten, M.; Kamper, U.; 
Dimmeler, S.; Zeiher, A. M. Reduced Number of Circulating Endothelial Progenitor 
Cells Predicts Future Cardiovascular Events: Proof of Concept for the Clinical 
Importance of Endogenous Vascular Repair. Circulation 2005, 111, 2981-2987. 
 (50)  Cao, Y.; Gomes, S. A.; Rangel, E. B.; Paulino, E. C.; Fonseca, T. L.; Li, J.; Teixeira, M. B.; 
Gouveia, C. H.; Bianco, A. C.; Kapiloff, M. S.; Balkan, W.; Hare, J. M. S-
Nitrosoglutathione Reductase-Dependent PPARgamma Denitrosylation Participates 
in MSC-Derived Adipogenesis and Osteogenesis. J. Clin. Invest 2015, 125, 1679-1691. 
 (51)  Jiang, Y.; Jahagirdar, B. N.; Reinhardt, R. L.; Schwartz, R. E.; Keene, C. D.; Ortiz-
Gonzalez, X. R.; Reyes, M.; Lenvik, T.; Lund, T.; Blackstad, M.; Du, J.; Aldrich, S.; 
Lisberg, A.; Low, W. C.; Largaespada, D. A.; Verfaillie, C. M. Pluripotency of 
Mesenchymal Stem Cells Derived From Adult Marrow. Nature 2002, 418, 41-49. 
 (52)  Chen, J.; Li, Y.; Katakowski, M.; Chen, X.; Wang, L.; Lu, D.; Lu, M.; Gautam, S. C.; Chopp, 
M. Intravenous Bone Marrow Stromal Cell Therapy Reduces Apoptosis and 
Promotes Endogenous Cell Proliferation After Stroke in Female Rat. J. Neurosci. Res. 
2003, 73, 778-786. 
 (53)  Hatzistergos, K. E.; Quevedo, H.; Oskouei, B. N.; Hu, Q.; Feigenbaum, G. S.; Margitich, I. 
S.; Mazhari, R.; Boyle, A. J.; Zambrano, J. P.; Rodriguez, J. E.; Dulce, R.; Pattany, P. M.; 
Valdes, D.; Revilla, C.; Heldman, A. W.; McNiece, I.; Hare, J. M. Bone Marrow 
Mesenchymal Stem Cells Stimulate Cardiac Stem Cell Proliferation and 
Differentiation. Circ. Res. 2010, 107, 913-922. 
 (54)  Bagno, L. L.; Kanashiro-Takeuchi, R. M.; Suncion, V. Y.; Golpanian, S.; Karantalis, V.; 
Wolf, A.; Wang, B.; Premer, C.; Balkan, W.; Rodriguez, J.; Valdes, D.; Rosado, M.; Block, 
N. L.; Goldstein, P.; Morales, A.; Cai, R. Z.; Sha, W.; Schally, A. V.; Hare, J. M. Growth 
Hormone-Releasing Hormone Agonists Reduce Myocardial Infarct Scar in Swine 
With Subacute Ischemic Cardiomyopathy. J. Am. Heart Assoc. 2015, 4. 

The CERES Trial  
 
Page 94 
  Oct 22, 2020 
ISCI / University of Miami Miller School of Medicine 
   **CONFIDENTIAL AND PROPRIETARY** 
 
 (55)  Premer, C.; Blum, A.; Bellio, M. A.; Schulman, I. H.; Hurwitz, B. E.; Parker, M.; 
Dermarkarian, C. R.; DiFede, D. L.; Balkan, W.; Khan, A.; Hare, J. M. Allogeneic 
Mesenchymal Stem Cells Restore Endothelial Function in Heart Failure by 
Stimulating Endothelial Progenitor Cells. EBioMedicine. 2015, 2, 467-475. 
 (56)  Mushtaq, M.; DiFede, D. L.; Golpanian, S.; Khan, A.; Gomes, S. A.; Mendizabal, A.; 
Heldman, A. W.; Hare, J. M. Rationale and Design of the Percutaneous Stem Cell 
Injection Delivery Effects on Neomyogenesis in Dilated Cardiomyopathy (the 
POSEIDON-DCM Study): a Phase I/II, Randomized Pilot Study of the Comparative 
Safety and Efficacy of Transendocardial Injection of Autologous Mesenchymal Stem 
Cell Vs. Allogeneic Mesenchymal Stem Cells in Patients With Non-Ischemic Dilated 
Cardiomyopathy. J. Cardiovasc. Transl. Res. 2014, 7, 769-780. 
 (57)  Pittenger, M. F.; Mackay, A. M.; Beck, S. C.; Jaiswal, R. K.; Douglas, R.; Mosca, J. D.; 
Moorman, M. A.; Simonetti, D. W.; Craig, S.; Marshak, D. R. Multilineage Potential of 
Adult Human Mesenchymal Stem Cells. Science 1999, 284, 143-147. 
 (58)  Ferreira-Martins, J.; Ogorek, B.; Cappetta, D.; Matsuda, A.; Signore, S.; D'Amario, D.; 
Kostyla, J.; Steadman, E.; Ide-Iwata, N.; Sanada, F.; Iaffaldano, G.; Ottolenghi, S.; 
Hosoda, T.; Leri, A.; Kajstura, J.; Anversa, P.; Rota, M. Cardiomyogenesis in the 
Developing Heart Is Regulated by C-Kit-Positive Cardiac Stem Cells. Circ. Res. 2012, 
110, 701-715. 
 (59)  Orlic, D.; Kajstura, J.; Chimenti, S.; Jakoniuk, I.; Anderson, S. M.; Li, B.; Pickel, J.; 
McKay, R.; Nadal-Ginard, B.; Bodine, D. M.; Leri, A.; Anversa, P. Bone Marrow Cells 
Regenerate Infarcted Myocardium. Nature 2001, 410, 701-705. 
 (60)  Salven, P.; Mustjoki, S.; Alitalo, R.; Alitalo, K.; Rafii, S. VEGFR-3 and CD133 Identify a 
Population of CD34+ Lymphatic/Vascular Endothelial Precursor Cells. Blood 2003, 
101, 168-172. 
 (61)  Reya, T.; Morrison, S. J.; Clarke, M. F.; Weissman, I. L. Stem Cells, Cancer, and Cancer 
Stem Cells. Nature 2001, 414, 105-111. 
 (62)  Asahara, T.; Murohara, T.; Sullivan, A.; Silver, M.; van der Zee, R.; Li, T.; 
Witzenbichler, B.; Schatteman, G.; Isner, J. M. Isolation of Putative Progenitor 
Endothelial Cells for Angiogenesis. Science 1997, 275, 964-967. 
 (63)  Asahara, T.; Masuda, H.; Takahashi, T.; Kalka, C.; Pastore, C.; Silver, M.; Kearne, M.; 
Magner, M.; Isner, J. M. Bone Marrow Origin of Endothelial Progenitor Cells 
Responsible for Postnatal Vasculogenesis in Physiological and Pathological 
Neovascularization. Circ. Res. 1999, 85, 221-228. 
 (64)  Gehling, U. M.; Ergun, S.; Schumacher, U.; Wagener, C.; Pantel, K.; Otte, M.; Schuch, G.; 
Schafhausen, P.; Mende, T.; Kilic, N.; Kluge, K.; Schafer, B.; Hossfeld, D. K.; Fiedler, W. 
In Vitro Differentiation of Endothelial Cells From AC133-Positive Progenitor Cells. 
Blood 2000, 95, 3106-3112. 

The CERES Trial  
 
Page 95 
  Oct 22, 2020 
ISCI / University of Miami Miller School of Medicine 
   **CONFIDENTIAL AND PROPRIETARY** 
 
 (65)  Peichev, M.; Naiyer, A. J.; Pereira, D.; Zhu, Z.; Lane, W. J.; Williams, M.; Oz, M. C.; 
Hicklin, D. J.; Witte, L.; Moore, M. A.; Rafii, S. Expression of VEGFR-2 and AC133 by 
Circulating Human CD34(+) Cells Identifies a Population of Functional Endothelial 
Precursors. Blood 2000, 95, 952-958. 
 (66)  Huss, R. Isolation of Primary and Immortalized CD34-Hematopoietic and 
Mesenchymal Stem Cells From Various Sources. Stem Cells. 2000, 18, 1-9. 
 (67)  Murry, C. E.; Soonpaa, M. H.; Reinecke, H.; Nakajima, H.; Nakajima, H. O.; Rubart, M.; 
Pasumarthi, K. B.; Virag, J. I.; Bartelmez, S. H.; Poppa, V.; Bradford, G.; Dowell, J. D.; 
Williams, D. A.; Field, L. J. Haematopoietic Stem Cells Do Not Transdifferentiate into 
Cardiac Myocytes in Myocardial Infarcts. Nature 2004, 428, 664-668. 
 (68)  Le, B. K.; Frassoni, F.; Ball, L.; Locatelli, F.; Roelofs, H.; Lewis, I.; Lanino, E.; Sundberg, 
B.; Bernardo, M. E.; Remberger, M.; Dini, G.; Egeler, R. M.; Bacigalupo, A.; Fibbe, W.; 
Ringden, O. Mesenchymal Stem Cells for Treatment of Steroid-Resistant, Severe, 
Acute Graft-Versus-Host Disease: a Phase II Study. Lancet 2008, 371, 1579-1586. 
 (69)  Lee, R. H.; Seo, M. J.; Reger, R. L.; Spees, J. L.; Pulin, A. A.; Olson, S. D.; Prockop, D. J. 
Multipotent Stromal Cells From Human Marrow Home to and Promote Repair of 
Pancreatic Islets and Renal Glomeruli in Diabetic NOD/Scid Mice. Proc. Natl. Acad. 
Sci. U. S. A. 2006, 103, 17438-17443. 
 (70)  Nemeth, K.; Leelahavanichkul, A.; Yuen, P. S.; Mayer, B.; Parmelee, A.; Doi, K.; Robey, 
P. G.; Leelahavanichkul, K.; Koller, B. H.; Brown, J. M.; Hu, X.; Jelinek, I.; Star, R. A.; 
Mezey, E. Bone Marrow Stromal Cells Attenuate Sepsis Via Prostaglandin E(2)-
Dependent Reprogramming of Host Macrophages to Increase Their Interleukin-10 
Production. Nat. Med. 2009, 15, 42-49. 
 (71)  Parekkadan, B.; van, P. D.; Suganuma, K.; Carter, E. A.; Berthiaume, F.; Tilles, A. W.; 
Yarmush, M. L. Mesenchymal Stem Cell-Derived Molecules Reverse Fulminant 
Hepatic Failure. PLoS. One. 2007, 2, e941. 
 (72)  Togel, F.; Hu, Z.; Weiss, K.; Isaac, J.; Lange, C.; Westenfelder, C. Administered 
Mesenchymal Stem Cells Protect Against Ischemic Acute Renal Failure Through 
Differentiation-Independent Mechanisms. Am. J. Physiol Renal Physiol 2005, 289, 
F31-F42. 
 (73)  Iso, Y.; Spees, J. L.; Serrano, C.; Bakondi, B.; Pochampally, R.; Song, Y. H.; Sobel, B. E.; 
Delafontaine, P.; Prockop, D. J. Multipotent Human Stromal Cells Improve Cardiac 
Function After Myocardial Infarction in Mice Without Long-Term Engraftment. 
Biochem. Biophys. Res. Commun. 2007, 354, 700-706. 
 (74)  Schuleri, K. H.; Feigenbaum, G. S.; Centola, M.; Weiss, E. S.; Zimmet, J. M.; Turney, J.; 
Kellner, J.; Zviman, M. M.; Hatzistergos, K. E.; Detrick, B.; Conte, J. V.; McNiece, I.; 
Steenbergen, C.; Lardo, A. C.; Hare, J. M. Autologous Mesenchymal Stem Cells 
Produce Reverse Remodelling in Chronic Ischaemic Cardiomyopathy. Eur. Heart J. 
2009, 30, 2722-2732. 

The CERES Trial  
 
Page 96 
  Oct 22, 2020 
ISCI / University of Miami Miller School of Medicine 
   **CONFIDENTIAL AND PROPRIETARY** 
 
 (75)  Miyahara, Y.; Nagaya, N.; Kataoka, M.; Yanagawa, B.; Tanaka, K.; Hao, H.; Ishino, K.; 
Ishida, H.; Shimizu, T.; Kangawa, K.; Sano, S.; Okano, T.; Kitamura, S.; Mori, H. 
Monolayered Mesenchymal Stem Cells Repair Scarred Myocardium After Myocardial 
Infarction. Nat. Med. 2006, 12, 459-465. 
 (76)  Hare, J. M.; Traverse, J. H.; Henry, T. D.; Dib, N.; Strumpf, R. K.; Schulman, S. P.; 
Gerstenblith, G.; DeMaria, A. N.; Denktas, A. E.; Gammon, R. S.; Hermiller, J. B., Jr.; 
Reisman, M. A.; Schaer, G. L.; Sherman, W. A Randomized, Double-Blind, Placebo-
Controlled, Dose-Escalation Study of Intravenous Adult Human Mesenchymal Stem 
Cells (Prochymal) After Acute Myocardial Infarction. J. Am. Coll. Cardiol. 2009, 54, 
2277-2286. 
 (77)  Gong, Z.; Niklason, L. E. Use of Human Mesenchymal Stem Cells As Alternative 
Source of Smooth Muscle Cells in Vessel Engineering. Methods Mol. Biol. 2011, 698, 
279-294. 
 (78)  Price, A. P.; England, K. A.; Matson, A. M.; Blazar, B. R.; Panoskaltsis-Mortari, A. 
Development of a Decellularized Lung Bioreactor System for Bioengineering the 
Lung: the Matrix Reloaded. Tissue Eng. Part A. 2010, 16, 2581-2591. 
 (79)  Williams, A. R.; Hare, J. M. Mesenchymal Stem Cells: Biology, Pathophysiology, 
Translational Findings, and Therapeutic Implications for Cardiac Disease. Circ. Res. 
2011, 109, 923-940. 
 (80)  Mangi, A. A.; Noiseux, N.; Kong, D.; He, H.; Rezvani, M.; Ingwall, J. S.; Dzau, V. J. 
Mesenchymal Stem Cells Modified With Akt Prevent Remodeling and Restore 
Performance of Infarcted Hearts. Nat. Med. 2003, 9, 1195-1201. 
 (81)  Williams, A. R.; Trachtenberg, B.; Velazquez, D. L.; McNiece, I.; Altman, P.; Rouy, D.; 
Mendizabal, A. M.; Pattany, P. M.; Lopera, G. A.; Fishman, J.; Zambrano, J. P.; Heldman, 
A. W.; Hare, J. M. Intramyocardial Stem Cell Injection in Patients With Ischemic 
Cardiomyopathy: Functional Recovery and Reverse Remodeling. Circ. Res. 2011, 
108, 792-796. 
 (82)  Ishizawa, K.; Kubo, H.; Yamada, M.; Kobayashi, S.; Numasaki, M.; Ueda, S.; Suzuki, T.; 
Sasaki, H. Bone Marrow-Derived Cells Contribute to Lung Regeneration After 
Elastase-Induced Pulmonary Emphysema. FEBS. Lett. 2004, 556, 249-252. 
 (83)  Spees, J. L.; Pociask, D. A.; Sullivan, D. E.; Whitney, M. J.; Lasky, J. A.; Prockop, D. J.; 
Brody, A. R. Engraftment of Bone Marrow Progenitor Cells in a Rat Model of 
Asbestos-Induced Pulmonary Fibrosis. Am. J. Respir. Crit Care Med. 2007, 176, 385-
394. 
 (84)  Spees, J. L.; Whitney, M. J.; Sullivan, D. E.; Lasky, J. A.; Laboy, M.; Ylostalo, J.; Prockop, 
D. J. Bone Marrow Progenitor Cells Contribute to Repair and Remodeling of the Lung 
and Heart in a Rat Model of Progressive Pulmonary Hypertension. FASEB J. 2008, 
22, 1226-1236. 

The CERES Trial  
 
Page 97 
  Oct 22, 2020 
ISCI / University of Miami Miller School of Medicine 
   **CONFIDENTIAL AND PROPRIETARY** 
 
 (85)  Bonfield, T. L.; Koloze, M.; Lennon, D. P.; Zuchowski, B.; Yang, S. E.; Caplan, A. I. 
Human Mesenchymal Stem Cells Suppress Chronic Airway Inflammation in the 
Murine Ovalbumin Asthma Model. Am. J. Physiol Lung Cell Mol. Physiol 2010, 299, 
L760-L770. 
 (86)  Lee, J. W.; Fang, X.; Gupta, N.; Serikov, V.; Matthay, M. A. Allogeneic Human 
Mesenchymal Stem Cells for Treatment of E. Coli Endotoxin-Induced Acute Lung 
Injury in the Ex Vivo Perfused Human Lung. Proc. Natl. Acad. Sci. U. S. A. 2009, 106, 
16357-16362. 
 (87)  Gao, J.; Dennis, J. E.; Muzic, R. F.; Lundberg, M.; Caplan, A. I. The Dynamic in Vivo 
Distribution of Bone Marrow-Derived Mesenchymal Stem Cells After Infusion. Cells. 
Tissues. Organs 2001, 169, 12-20. 
 (88)  Cargnoni, A.; Gibelli, L.; Tosini, A.; Signoroni, P. B.; Nassuato, C.; Arienti, D.; 
Lombardi, G.; Albertini, A.; Wengler, G. S.; Parolini, O. Transplantation of Allogeneic 
and Xenogeneic Placenta-Derived Cells Reduces Bleomycin-Induced Lung Fibrosis. 
Cell Transplant. 2009, 18, 405-422. 
 (89)  Ortiz, L. A.; Gambelli, F.; McBride, C.; Gaupp, D.; Baddoo, M.; Kaminski, N.; Phinney, D. 
G. Mesenchymal Stem Cell Engraftment in Lung Is Enhanced in Response to 
Bleomycin Exposure and Ameliorates Its Fibrotic Effects. Proc. Natl. Acad. Sci. U. S. A. 
2003, 100, 8407-8411. 
 (90)  Moodley, Y.; Atienza, D.; Manuelpillai, U.; Samuel, C. S.; Tchongue, J.; Ilancheran, S.; 
Boyd, R.; Trounson, A. Human Umbilical Cord Mesenchymal Stem Cells Reduce 
Fibrosis of Bleomycin-Induced Lung Injury. Am. J. Pathol. 2009, 175, 303-313. 
 (91)  Ahn, M. H.; Park, B. L.; Lee, S. H.; Park, S. W.; Park, J. S.; Kim, D. J.; Jang, A. S.; Park, J. S.; 
Shin, H. K.; Uh, S. T.; Kim, Y. K.; Kim, Y. W.; Han, S. K.; Jung, K. S.; Lee, K. Y.; Jeong, S. H.; 
Park, J. W.; Choi, B. W.; Park, I. W.; Chung, M. P.; Shin, H. D.; Song, J. W.; Kim, D. S.; 
Park, C. S.; Shim, Y. S. A Promoter SNP Rs4073T>A in the Common Allele of the 
Interleukin 8 Gene Is Associated With the Development of Idiopathic Pulmonary 
Fibrosis Via the IL-8 Protein Enhancing Mode. Respir. Res. 2011, 12, 73. 
 (92)  Kim, D. Y.; Kwon, E. Y.; Hong, G. U.; Lee, Y. S.; Lee, S. H.; Ro, J. Y. Cigarette Smoke 
Exacerbates Mouse Allergic Asthma Through Smad Proteins Expressed in Mast Cells. 
Respir. Res. 2011, 12, 49. 
 (93)  Lee, S. H.; Jang, A. S.; Kim, Y. E.; Cha, J. Y.; Kim, T. H.; Jung, S.; Park, S. K.; Lee, Y. K.; 
Won, J. H.; Kim, Y. H.; Park, C. S. Modulation of Cytokine and Nitric Oxide by 
Mesenchymal Stem Cell Transfer in Lung Injury/Fibrosis. Respir. Res. 2010, 11, 16. 
 (94)  Rojas, M.; Xu, J.; Woods, C. R.; Mora, A. L.; Spears, W.; Roman, J.; Brigham, K. L. Bone 
Marrow-Derived Mesenchymal Stem Cells in Repair of the Injured Lung. Am. J. 
Respir. Cell Mol. Biol. 2005, 33, 145-152. 

The CERES Trial  
 
Page 98 
  Oct 22, 2020 
ISCI / University of Miami Miller School of Medicine 
   **CONFIDENTIAL AND PROPRIETARY** 
 
 (95)  Lee, O. K.; Kuo, T. K.; Chen, W. M.; Lee, K. D.; Hsieh, S. L.; Chen, T. H. Isolation of 
Multipotent Mesenchymal Stem Cells From Umbilical Cord Blood 3. Blood 2004, 
103, 1669-1675. 
 (96)  Lee, S. H.; Jang, A. S.; Kim, Y. E.; Cha, J. Y.; Kim, T. H.; Jung, S.; Park, S. K.; Lee, Y. K.; 
Won, J. H.; Kim, Y. H.; Park, C. S. Modulation of Cytokine and Nitric Oxide by 
Mesenchymal Stem Cell Transfer in Lung Injury/Fibrosis. Respir. Res. 2010, 11, 16. 
 (97)  Liang, J.; Zhang, H.; Hua, B.; Wang, H.; Lu, L.; Shi, S.; Hou, Y.; Zeng, X.; Gilkeson, G. S.; 
Sun, L. Allogenic Mesenchymal Stem Cells Transplantation in Refractory Systemic 
Lupus Erythematosus: a Pilot Clinical Study. Ann. Rheum. Dis. 2010, 69, 1423-1429. 
 (98)  Lu, L. L.; Liu, Y. J.; Yang, S. G.; Zhao, Q. J.; Wang, X.; Gong, W.; Han, Z. B.; Xu, Z. S.; Lu, Y. 
X.; Liu, D.; Chen, Z. Z.; Han, Z. C. Isolation and Characterization of Human Umbilical 
Cord Mesenchymal Stem Cells With Hematopoiesis-Supportive Function and Other 
Potentials. Haematologica 2006, 91, 1017-1026. 
 (99)  Moodley, Y.; Atienza, D.; Manuelpillai, U.; Samuel, C. S.; Tchongue, J.; Ilancheran, S.; 
Boyd, R.; Trounson, A. Human Umbilical Cord Mesenchymal Stem Cells Reduce 
Fibrosis of Bleomycin-Induced Lung Injury. Am. J. Pathol. 2009, 175, 303-313. 
(100)  Ortiz, L. A.; Gambelli, F.; McBride, C.; Gaupp, D.; Baddoo, M.; Kaminski, N.; Phinney, D. 
G. Mesenchymal Stem Cell Engraftment in Lung Is Enhanced in Response to 
Bleomycin Exposure and Ameliorates Its Fibrotic Effects. Proc. Natl. Acad. Sci. U. S. A. 
2003, 100, 8407-8411. 
(101)  Rojas, M.; Xu, J.; Woods, C. R.; Mora, A. L.; Spears, W.; Roman, J.; Brigham, K. L. Bone 
Marrow-Derived Mesenchymal Stem Cells in Repair of the Injured Lung. Am. J. 
Respir. Cell Mol. Biol. 2005, 33, 145-152. 
(102)  Romanov, Y. A.; Svintsitskaya, V. A.; Smirnov, V. N. Searching for Alternative Sources 
of Postnatal Human Mesenchymal Stem Cells: Candidate MSC-Like Cells From 
Umbilical Cord 1. Stem Cells 2003, 21, 105-110. 
(103)  Wexler, S. A.; Donaldson, C.; Denning-Kendall, P.; Rice, C.; Bradley, B.; Hows, J. M. 
Adult Bone Marrow Is a Rich Source of Human Mesenchymal 'Stem' Cells but 
Umbilical Cord and Mobilized Adult Blood Are Not 1. Br. J. Haematol. 2003, 121, 
368-374. 
(104)  Baksh, D.; Yao, R.; Tuan, R. S. Comparison of Proliferative and Multilineage 
Differentiation Potential of Human Mesenchymal Stem Cells Derived From Umbilical 
Cord and Bone Marrow 1. Stem Cells 2007, 25, 1384-1392. 
(105)  Aigner, J.; Eblenkamp, M.; Wintermantel, E. [Techniques for Functional Tissue and 
Organ Replacement Using Postnatal Stem Cells] 3. Chirurg 2005, 76, 435-444. 

The CERES Trial  
 
Page 99 
  Oct 22, 2020 
ISCI / University of Miami Miller School of Medicine 
   **CONFIDENTIAL AND PROPRIETARY** 
 
(106)  Eblenkamp, M.; Aigner, J.; Hintermair, J.; Potthoff, S.; Hopfner, U.; Jacobs, V.; 
Niemeyer, M.; Wintermantel, E. [Umbilical Cord Stromal Cells (UCSC). Cells 
Featuring Osteogenic Differentiation Potential] 1. Orthopade 2004, 33, 1338-1345. 
(107)  Kestendjieva, S.; Kyurkchiev, D.; Tsvetkova, G.; Mehandjiev, T.; Dimitrov, A.; Nikolov, 
A.; Kyurkchiev, S. Characterization of Mesenchymal Stem Cells Isolated From the 
Human Umbilical Cord 1. Cell Biol. Int. 2008, 32, 724-732. 
(108)  Mitchell, K. E.; Weiss, M. L.; Mitchell, B. M.; Martin, P.; Davis, D.; Morales, L.; Helwig, 
B.; Beerenstrauch, M.; Abou-Easa, K.; Hildreth, T.; Troyer, D.; Medicetty, S. Matrix 
Cells From Wharton's Jelly Form Neurons and Glia. Stem Cells 2003, 21, 50-60. 
(109)  Weiss, M. L.; Anderson, C.; Medicetty, S.; Seshareddy, K. B.; Weiss, R. J.; VanderWerff, 
I.; Troyer, D.; McIntosh, K. R. Immune Properties of Human Umbilical Cord 
Wharton's Jelly-Derived Cells 1. Stem Cells 2008, 26, 2865-2874. 
(110)  Wang, H. S.; Hung, S. C.; Peng, S. T.; Huang, C. C.; Wei, H. M.; Guo, Y. J.; Fu, Y. S.; Lai, M. 
C.; Chen, C. C. Mesenchymal Stem Cells in the Wharton's Jelly of the Human Umbilical 
Cord 2. Stem Cells 2004, 22, 1330-1337. 
(111)  Newman, A. B.; Gottdiener, J. S.; McBurnie, M. A.; Hirsch, C. H.; Kop, W. J.; Tracy, R.; 
Walston, J. D.; Fried, L. P. Associations of Subclinical Cardiovascular Disease With 
Frailty. J. Gerontol. A Biol. Sci. Med. Sci. 2001, 56, M158-M166. 
(112)  Hollweck, T.; Hagl, C.; Eissner, G. Mesenchymal Stem Cells From Umbilical Cord 
Tissue As Potential Therapeutics for Cardiomyodegenerative Diseases - a Review. 
Int. J. Mol. Cell Med. 2012, 1, 119-132. 
(113)  Secco, M.; Zucconi, E.; Vieira, N. M.; Fogaca, L. L.; Cerqueira, A.; Carvalho, M. D.; 
Jazedje, T.; Okamoto, O. K.; Muotri, A. R.; Zatz, M. Multipotent Stem Cells From 
Umbilical Cord: Cord Is Richer Than Blood! Stem Cells 2008, 26, 146-150. 
(114)  Troyer, D. L.; Weiss, M. L. Wharton's Jelly-Derived Cells Are a Primitive Stromal Cell 
Population 4. Stem Cells 2008, 26, 591-599. 
(115)  Chao, Y. H.; Wu, H. P.; Chan, C. K.; Tsai, C.; Peng, C. T.; Wu, K. H. Umbilical Cord-
Derived Mesenchymal Stem Cells for Hematopoietic Stem Cell Transplantation 2. J. 
Biomed. Biotechnol. 2012, 2012, 759503. 
(116)  Kouroupis, D.; Churchman, S. M.; English, A.; Emery, P.; Giannoudis, P. V.; McGonagle, 
D.; Jones, E. A. Assessment of Umbilical Cord Tissue As a Source of Mesenchymal 
Stem Cell/Endothelial Cell Mixtures for Bone Regeneration 2. Regen. Med. 2013, 8, 
569-581. 
(117)  Wu, K. H.; Chan, C. K.; Tsai, C.; Chang, Y. H.; Sieber, M.; Chiu, T. H.; Ho, M.; Peng, C. T.; 
Wu, H. P.; Huang, J. L. Effective Treatment of Severe Steroid-Resistant Acute Graft-
Versus-Host Disease With Umbilical Cord-Derived Mesenchymal Stem Cells 3. 
Transplantation 2011, 91, 1412-1416. 

The CERES Trial  
 
Page 100 
  Oct 22, 2020 
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   **CONFIDENTIAL AND PROPRIETARY** 
 
(118)  Sun, L.; Wang, D.; Liang, J.; Zhang, H.; Feng, X.; Wang, H.; Hua, B.; Liu, B.; Ye, S.; Hu, X.; 
Xu, W.; Zeng, X.; Hou, Y.; Gilkeson, G. S.; Silver, R. M.; Lu, L.; Shi, S. Umbilical Cord 
Mesenchymal Stem Cell Transplantation in Severe and Refractory Systemic Lupus 
Erythematosus. Arthritis Rheum. 2010, 62, 2467-2475. 
(119)  Liang, J.; Zhang, H.; Hua, B.; Wang, H.; Lu, L.; Shi, S.; Hou, Y.; Zeng, X.; Gilkeson, G. S.; 
Sun, L. Allogenic Mesenchymal Stem Cells Transplantation in Refractory Systemic 
Lupus Erythematosus: a Pilot Clinical Study. Ann. Rheum. Dis. 2010, 69, 1423-1429. 
(120)  Lee, O. K.; Kuo, T. K.; Chen, W. M.; Lee, K. D.; Hsieh, S. L.; Chen, T. H. Isolation of 
Multipotent Mesenchymal Stem Cells From Umbilical Cord Blood 
3. Blood 2004, 103, 1669-1675. 
(121)  Romanov, Y. A.; Svintsitskaya, V. A.; Smirnov, V. N. Searching for Alternative Sources 
of Postnatal Human Mesenchymal Stem Cells: Candidate MSC-Like Cells From 
Umbilical Cord 
1. Stem Cells 2003, 21, 105-110. 
(122)  Wexler, S. A.; Donaldson, C.; Denning-Kendall, P.; Rice, C.; Bradley, B.; Hows, J. M. 
Adult Bone Marrow Is a Rich Source of Human Mesenchymal 'Stem' Cells but 
Umbilical Cord and Mobilized Adult Blood Are Not 
1. Br. J. Haematol. 2003, 121, 368-374. 
(123)  Baksh, D.; Yao, R.; Tuan, R. S. Comparison of Proliferative and Multilineage 
Differentiation Potential of Human Mesenchymal Stem Cells Derived From Umbilical 
Cord and Bone Marrow 
1. Stem Cells 2007, 25, 1384-1392. 
(124)  Aigner, J.; Eblenkamp, M.; Wintermantel, E. [Techniques for Functional Tissue and 
Organ Replacement Using Postnatal Stem Cells] 
3. Chirurg 2005, 76, 435-444. 
(125)  Eblenkamp, M.; Aigner, J.; Hintermair, J.; Potthoff, S.; Hopfner, U.; Jacobs, V.; 
Niemeyer, M.; Wintermantel, E. [Umbilical Cord Stromal Cells (UCSC). Cells 
Featuring Osteogenic Differentiation Potential] 
1. Orthopade 2004, 33, 1338-1345. 
(126)  Kestendjieva, S.; Kyurkchiev, D.; Tsvetkova, G.; Mehandjiev, T.; Dimitrov, A.; Nikolov, 
A.; Kyurkchiev, S. Characterization of Mesenchymal Stem Cells Isolated From the 
Human Umbilical Cord 
1. Cell Biol. Int. 2008, 32, 724-732. 
(127)  Weiss, M. L.; Anderson, C.; Medicetty, S.; Seshareddy, K. B.; Weiss, R. J.; VanderWerff, 
I.; Troyer, D.; McIntosh, K. R. Immune Properties of Human Umbilical Cord 
Wharton's Jelly-Derived Cells 
1. Stem Cells 2008, 26, 2865-2874. 

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(128)  Wang, H. S.; Hung, S. C.; Peng, S. T.; Huang, C. C.; Wei, H. M.; Guo, Y. J.; Fu, Y. S.; Lai, M. 
C.; Chen, C. C. Mesenchymal Stem Cells in the Wharton's Jelly of the Human Umbilical 
Cord 
2. Stem Cells 2004, 22, 1330-1337. 
(129)  Troyer, D. L.; Weiss, M. L. Wharton's Jelly-Derived Cells Are a Primitive Stromal Cell 
Population 
4. Stem Cells 2008, 26, 591-599. 
(130)  Wu, K. H.; Chan, C. K.; Tsai, C.; Chang, Y. H.; Sieber, M.; Chiu, T. H.; Ho, M.; Peng, C. T.; 
Wu, H. P.; Huang, J. L. Effective Treatment of Severe Steroid-Resistant Acute Graft-
Versus-Host Disease With Umbilical Cord-Derived Mesenchymal Stem Cells 
3. Transplantation 2011, 91, 1412-1416. 
(131)  Chao, Y. H.; Wu, H. P.; Chan, C. K.; Tsai, C.; Peng, C. T.; Wu, K. H. Umbilical Cord-
Derived Mesenchymal Stem Cells for Hematopoietic Stem Cell Transplantation 
2. J. Biomed. Biotechnol. 2012, 2012, 759503. 
(132)  Kouroupis, D.; Churchman, S. M.; English, A.; Emery, P.; Giannoudis, P. V.; McGonagle, 
D.; Jones, E. A. Assessment of Umbilical Cord Tissue As a Source of Mesenchymal 
Stem Cell/Endothelial Cell Mixtures for Bone Regeneration 
2. Regen. Med. 2013, 8, 569-581. 
(133)  Koh, S. H.; Kim, K. S.; Choi, M. R.; Jung, K. H.; Park, K. S.; Chai, Y. G.; Roh, W.; Hwang, S. 
J.; Ko, H. J.; Huh, Y. M.; Kim, H. T.; Kim, S. H. Implantation of Human Umbilical Cord-
Derived Mesenchymal Stem Cells As a Neuroprotective Therapy for Ischemic Stroke 
in Rats. Brain Res. 2008, 1229, 233-248. 
(134)  Sundin, M.; Orvell, C.; Rasmusson, I.; Sundberg, B.; Ringden, O.; Le, B. K. 
Mesenchymal Stem Cells Are Susceptible to Human Herpesviruses, but Viral DNA 
Cannot Be Detected in the Healthy Seropositive Individual 
5. Bone Marrow Transplant. 2006, 37, 1051-1059.