bluuebunny/crossref_metadata_2025_split huggingface dataset:
From Skin Biopsy to Neurons Through a Pluripotent Intermediate Under Good Manufacturing Practice Protocols
Authors: Karumbayaram Saravanan , Lee Peiyee , Azghadi Soheila F. , Cooper Aaron R. , Patterson Michaela , Kohn Donald B. , Pyle April , Clark Amander , Byrne James , Zack Jerome A. , Plath Kathrin , Lowry William E. 
Published: May 2012

Abstract
The clinical application of human-induced pluripotent stem cells (hiPSCs) requires not only the production of Good Manufacturing Practice-grade (GMP-grade) hiPSCs but also the derivation of specified cell types for transplantation under GMP conditions. Previous reports have suggested that hiPSCs can be produced in the absence of animal-derived reagents (xenobiotics) to ease the transition to production under GMP standards. However, to facilitate the use of hiPSCs in cell-based therapeutics, their progeny should be produced not only in the absence of xenobiotics but also under GMP conditions requiring extensive standardization of protocols, documentation, and reproducibility of methods and product. Here, we present a successful framework to produce GMP-grade derivatives of hiPSCs that are free of xenobiotic exposure from the collection of patient fibroblasts, through reprogramming, maintenance of hiPSCs, identification of reprogramming vector integration sites (nrLAM-PCR), and finally specification and terminal differentiation of clinically relevant cells. Furthermore, we developed a primary set of Standard Operating Procedures for the GMP-grade derivation and differentiation of these cells as a resource to facilitate widespread adoption of these practices.
Sp1 Transcription Factor Interaction with Accumulated Prelamin A Impairs Adipose Lineage Differentiation in Human Mesenchymal Stem Cells: Essential Role of Sp1 in the Integrity of Lipid Vesicles
Authors: Ruiz de Eguino Garbiñe , Infante Arantza , Schlangen Karin , Aransay Ana M. , Fullaondo Ane , Soriano Mario , García-Verdugo José Manuel , Martín Ángel G. , Rodríguez Clara I. 
Published: May 2012

Abstract
Lamin A (LMNA)-linked lipodystrophies may be either genetic (associated with LMNA mutations) or acquired (associated with the use of human immunodeficiency virus protease inhibitors [PIs]), and in both cases they share clinical features such as anomalous distribution of body fat or generalized loss of adipose tissue, metabolic alterations, and early cardiovascular complications. Both LMNA-linked lipodystrophies are characterized by the accumulation of the lamin A precursor prelamin A. The pathological mechanism by which prelamin A accumulation induces the lipodystrophy associated phenotypes remains unclear. Since the affected tissues in these disorders are of mesenchymal origin, we have generated an LMNA-linked experimental model using human mesenchymal stem cells treated with a PI, which recapitulates the phenotypes observed in patient biopsies. This model has been demonstrated to be a useful tool to unravel the pathological mechanism of the LMNA-linked lipodystrophies, providing an ideal system to identify potential targets to generate new therapies for drug discovery screening. We report for the first time that impaired adipogenesis is a consequence of the interaction between accumulated prelamin A and Sp1 transcription factor, sequestration of which results in altered extracellular matrix gene expression. In fact, our study shows a novel, essential, and finely tuned role for Sp1 in adipose lineage differentiation in human mesenchymal stem cells. These findings define a new physiological experimental model to elucidate the pathological mechanisms LMNA-linked lipodystrophies, creating new opportunities for research and treatment not only of LMNA-linked lipodystrophies but also of other adipogenesis-associated metabolic diseases.
The Effect of Extended First Passage Culture on the Proliferation and Differentiation of Human Marrow-Derived Mesenchymal Stem Cells
Authors: Lennon Donald P. , Schluchter Mark D. , Caplan Arnold I. 
Published: May 2012

Abstract
Human marrow-derived mesenchymal stem cells (hMSCs) have been investigated for more than 20 years. They have been shown to be therapeutic in a number of animal models and are currently in use in more than 200 clinical trials, thus documenting their importance in the field of translational medicine. Standard protocols for the passage and collection of hMSCs involve trypsinization of preconfluent cultures. This practice is based, at least in part, on concerns that the multipotency of these cells would be diminished if the cultures became confluent. To test this concern, hMSCs were isolated and maintained in standard culture conditions in primary culture and were then subcultured after 2 weeks. The resulting first passage cultures were divided into two groups: those that were subcultured at the normal frequency, usually at 7 days for each passage (referred to as standard conditions [SC]), and those that were maintained for up to 53 days without being further subcultured (extended first passage [EFP]). At the end of the second passage and each of five subsequent subcultures for cells in SC (i.e., through passage 7), complementary EFP cultures were also trypsinized. Cells from each group were counted, resuspended in serum-free medium, and assayed to determine the ability of the cells to differentiate along osteogenic, chondrogenic, and adipogenic lineages. Cells in SC experienced an average of 27 population doublings through seven passages, whereas hMSCs in EFP achieved approximately 16 population doublings after 34 days but demonstrated very little increase in cell number after that time. The ability of hMSCs in EFP to produce bone in ceramic cubes implanted subcutaneously in immunocompromised mice and to differentiate into cartilage in pellet or aggregate culture was at least equivalent to that of the cells in SC through seven passages, whereas the capacity of the EFP hMSCs to produce lipid droplets in adipogenic conditions was maintained but was diminished relative to that of SC cells.
Concise Review: The Role of Clinical Trials in Deciphering Mechanisms of Action of Cardiac Cell-Based Therapy
Authors: Suncion Viky Y. , Schulman Ivonne H. , Hare Joshua M. 
Published: May 2012

Abstract
Although the initial promise of cardiac cell-based therapy was based on the concept that stem cells engraft into diseased tissue and differentiate into beating cardiomyocytes, it is now clear that successful cell-based tissue repair involves a more complex orchestration of cellular and molecular events. Many lessons about successful tissue repair can be gleaned from the results of early-stage clinical trials. This body of work shows that cell-based therapy (with various cell sources and delivery methods) effectively prevents and reverses the remodeling process, the sine qua non of the myocardial injury reaction and anatomic substrate for subsequent clinical events. The potentially favorable remodeling responses to cell therapy have prompted a search for mechanisms of action beyond cell repopulation and guided future clinical trial design by providing more clear focus on pathophysiological endpoints signifying favorable responses to cell-based therapy. Perhaps the most important mechanistic insight is that endogenous stem/precursor cells have the potential to participate in tissue healing. With regard to the phenotype of cellular response, it is clear that parameters of remodeling, such as infarct size and ventricular dimensions, should be directly measured, thereby necessitating the use of sophisticated imaging modalities, such as cardiac magnetic resonance imaging or multidetector computed tomography. These new insights offer an optimistic outlook on the state of cell-based therapeutics for cardiac disease and suggest that pivotal clinical trials are warranted. Here, we review lessons learned from clinical trials and evaluate the choice and assessment of endpoints to best predict efficacy of cell therapy.
Increased Potency of Cardiac Stem Cells Compared with Bone Marrow Mesenchymal Stem Cells in Cardiac Repair
Authors: Oskouei Behzad N. , Lamirault Guillaume , Joseph Chacko , Treuer Adriana V. , Landa Stephanie , Da Silva Jose , Hatzistergos Konstantinos , Dauer Marc , Balkan Wayne , McNiece Ian , Hare Joshua M. 
Published: May 2012

Abstract
Whereas cardiac-derived c-kit+ stem cells (CSCs) and bone marrow-derived mesenchymal stem cells (MSCs) are undergoing clinical trials testing safety and efficacy as a cell-based therapy, the relative therapeutic and biologic efficacy of these two cell types is unknown. We hypothesized that human CSCs have greater ability than MSCs to engraft, differentiate, and improve cardiac function. We compared intramyocardial injection of human fetal CSCs (36,000) with two doses of adult MSCs (36,000 and 1,000,000) or control (phosphate buffered saline) in nonobese diabetic/severe combined immune deficiency mice after coronary artery ligation. The myocardial infarction-induced enlargement in left ventricular chamber dimensions was ameliorated by CSCs (p &lt; .05 for diastolic and systolic volumes), as was the decline in ejection fraction (EF; p &lt; .05). Whereas 1 × 106 MSCs partially ameliorated ventricular remodeling and improved EF to a similar degree as CSCs, 36,000 MSCs did not influence chamber architecture or function. All cell therapies improved myocardial contractility, but CSCs preferentially reduced scar size and reduced vascular afterload. Engraftment and trilineage differentiation was substantially greater with CSCs than with MSCs. Adult-cultured c-kit+CSCs were less effective than fetal, but were still more potent than high-dose MSCs. These data demonstrate enhanced CSC engraftment, differentiation, and improved cardiac remodeling and function in ischemic heart failure. MSCs required a 30-fold greater dose than CSCs to improve cardiac function and anatomy. Together, these findings demonstrate a greater potency of CSCs than bone marrow MSCs in cardiac repair.
Concise Review: Role of Mesenchymal Stem Cells in Wound Repair
Authors: Maxson Scott , Lopez Erasmo A. , Yoo Dana , Danilkovitch-Miagkova Alla , LeRoux Michelle A. 
Published: May 2012

AbstractWound healing requires a coordinated interplay among cells, growth factors, and extracellular matrix proteins. Central to this process is the endogenous mesenchymal stem cell (MSC), which coordinates the repair response by recruiting other host cells and secreting growth factors and matrix proteins. MSCs are self-renewing multipotent stem cells that can differentiate into various lineages of mesenchymal origin such as bone, cartilage, tendon, and fat. In addition to multilineage differentiation capacity, MSCs regulate immune response and inflammation and possess powerful tissue protective and reparative mechanisms, making these cells attractive for treatment of different diseases. The beneficial effect of exogenous MSCs on wound healing was observed in a variety of animal models and in reported clinical cases. Specifically, they have been successfully used to treat chronic wounds and stimulate stalled healing processes. Recent studies revealed that human placental membranes are a rich source of MSCs for tissue regeneration and repair. This review provides a concise summary of current knowledge of biological properties of MSCs and describes the use of MSCs for wound healing. In particular, the scope of this review focuses on the role MSCs have in each phase of the wound-healing process. In addition, characterization of MSCs containing skin substitutes is described, demonstrating the presence of key growth factors and cytokines uniquely suited to aid in wound repair.
Concise Review: Personalized Human Bone Grafts for Reconstructing Head and Face
Authors: Bhumiratana Sarindr , Vunjak-Novakovic Gordana 
Published: May 2012

Abstract
Regeneration of normal shape, architecture, and function of craniofacial tissues following congenital abnormality, trauma, or surgical treatment presents special problems to tissue engineering. Because of the great variations in properties of these tissues, currently available treatment options fall short of adequate care. We propose that the engineering of personalized bone graft customized to the patient and the specific clinical condition would revolutionize the way we currently treat craniofacial defects and discuss some of the current and emerging treatment modalities.
Concise Review: Clinical Translation of Wound Healing Therapies Based on Mesenchymal Stem Cells
Authors: Jackson Wesley M. , Nesti Leon J. , Tuan Rocky S. 
Published: May 2012

Abstract
There is enormous worldwide demand for therapies to promote the efficient resolution of hard-to-heal wounds with minimal appearance of scarring. Recent in vitro studies with mesenchymal stem cells (MSCs) have identified numerous mechanisms by which these cells can promote the process of wound healing, and there is significant interest in the clinical translation of an MSC-based therapy to promote dermal regeneration. This review provides a systematic analysis of recent preclinical and clinical research to evaluate the use of MSCs in wound healing applications. These in vivo studies provide overwhelming evidence that MSCs can accelerate wound closure by modulating the inflammatory environment, promoting the formation of a well-vascularized granulation matrix, encouraging the migration of keratinocytes, and inhibiting apoptosis of wound healing cells. The trophic effects of MSC therapy also appear to augment wound healing in diabetic tissues, thereby preventing the formation of nonhealing ulcers. Finally, a number of delivery systems have been evaluated and indicate that MSCs could be the basis of a versatile therapy to fulfill the clinical needs for dermal regeneration. However, despite the apparent advantages of MSC-based therapies, there have been only limited clinical investigations of this type of therapy in humans. Thus, our review concludes with a discussion of the translational barriers that are limiting the widespread clinical use of MSCs to enhance wound healing.
Concise Review: Pancreas Regeneration: Recent Advances and Perspectives
Authors: Lysy Philippe A. , Weir Gordon C. , Bonner-Weir Susan 
Published: May 2012

Abstract
The replacement of functional pancreatic β-cells is seen as an attractive potential therapy for diabetes, because diabetes results from an inadequate β-cell mass. Inducing replication of the remaining β-cells and new islet formation from progenitors within the pancreas (neogenesis) are the most direct ways to increase the β-cell mass. Stimulation of both replication and neogenesis have been reported in rodents, but their clinical significance must still be shown. Because human islet transplantation is limited by the scarcity of donors and graft failure within a few years, efforts have recently concentrated on the use of stem cells to replace the deficient β-cells. Currently, embryonic stem cells and induced pluripotent stem cells achieve high levels of β-cell differentiation, but their clinical use is still hampered by ethical issues and/or the risk of developing tumors after transplantation. Pancreatic epithelial cells (duct, acinar, or α-cells) represent an appealing alternative to stem cells because they demonstrate β-cell differentiation capacities. Yet translation of such capacity to human cells after significant in vitro expansion has yet to be achieved. Besides providing new β-cells, cell therapy also has to address the question on how to protect the transplanted cells from destruction by the immune system via either allo- or autoimmunity. Encouraging developments have been made in encapsulation and immunomodulation techniques, but many challenges still remain. Herein, we discuss recent advances in the search for β-cell replacement therapies, current strategies for circumventing the immune system, and mandatory steps for new techniques to be translated from bench to clinics.
Embryonic Stem Cell-Based Cardiopatches Improve Cardiac Function in Infarcted Rats
Authors: Vallée Jean-Paul , Hauwel Mathieu , Lepetit-Coiffé Matthieu , Bei Wang , Montet-Abou Karin , Meda Paolo , Gardier Stephany , Zammaretti Prisca , Kraehenbuehl Thomas P. , Herrmann Francois , Hubbell Jeffrey A. , Jaconi Marisa E. 
Published: May 2012

Abstract
Pluripotent stem cell-seeded cardiopatches hold promise for in situ regeneration of infarcted hearts. Here, we describe a novel cardiopatch based on bone morphogenetic protein 2-primed cardiac-committed mouse embryonic stem cells, embedded into biodegradable fibrin matrices and engrafted onto infarcted rat hearts. For in vivo tracking of the engrafted cardiac-committed cells, superparamagnetic iron oxide nanoparticles were magnetofected into the cells, thus enabling detection and functional evaluation by high-resolution magnetic resonance imaging. Six weeks after transplantation into infarcted rat hearts, both local (p &lt; .04) and global (p &lt; .015) heart function, as well as the left ventricular dilation (p &lt; .0011), were significantly improved (p &lt; .001) as compared with hearts receiving cardiopatches loaded with iron nanoparticles alone. Histological analysis revealed that the fibrin scaffolds had degraded over time and clusters of myocyte enhancer factor 2-positive cardiac-committed cells had colonized most of the infarcted myocardium, including the fibrotic area. De novo CD31-positive blood vessels were formed in the vicinity of the transplanted cardiopatch. Altogether, our data provide evidence that stem cell-based cardiopatches represent a promising therapeutic strategy to achieve efficient cell implantation and improved global and regional cardiac function after myocardial infarction.
Stimulation of Skin and Wound Fibroblast Migration by Mesenchymal Stem Cells Derived from Normal Donors and Chronic Wound Patients
Authors: Rodriguez-Menocal Luis , Salgado Marcela , Ford Dwayne , Van Badiavas Evangelos 
Published: May 2012

Abstract
Chronic wounds continue to be a major cause of morbidity for patients and an economic burden on the health care system. Novel therapeutic approaches to improved wound healing will need, however, to address cellular changes induced by a number of systemic comorbidities seen in chronic wound patients, such as diabetes, chronic renal failure, and arterial or venous insufficiency. These effects likely include impaired inflammatory cell migration, reduced growth factor production, and poor tissue remodeling. The multifunctional properties of bone marrow-derived mesenchymal stem cells (MSCs), including their ability to differentiate into various cell types and capacity to secrete factors important in accelerating healing of cutaneous wounds, have made MSCs a promising agent for tissue repair and regeneration. In this study we have used an in vitro scratch assay procedure incorporating labeled MSCs and fibroblasts derived from normal donors and chronic wound patients in order to characterize the induction of mobilization when these cells are mixed. A modified Boyden chamber assay was also used to examine the effect of soluble factors on fibroblast migration. These studies suggest that MSCs play a role in skin wound closure by affecting dermal fibroblast migration in a dose-dependent manner. Deficiencies were noted, however, in chronic wound patient fibroblasts and MSCs as compared with those derived from normal donors. These findings provide a foundation to develop therapies targeted specifically to the use of bone marrow-derived MSCs in wound healing and may provide insight into why some wounds do not heal.
Magnetic Resonance Imaging and Fluorescence Labeling of Clinical-Grade Mesenchymal Stem Cells Without Impacting Their Phenotype: Study in a Rat Model of Stroke
Authors: Detante Olivier , Valable Samuel , de Fraipont Florence , Grillon Emmanuelle , Barbier Emmanuel Luc , Moisan Anaïck , Arnaud Josiane , Moriscot Christine , Segebarth Christoph , Hommel Marc , Remy Chantal , Richard Marie-Jeanne 
Published: May 2012

Abstract
Human mesenchymal stem cells (hMSCs) have strong potential for cell therapy after stroke. Tracking stem cells in vivo following a graft can provide insight into many issues regarding optimal route and/or dosing. hMSCs were labeled for magnetic resonance imaging (MRI) and histology with micrometer-sized superparamagnetic iron oxides (M-SPIOs) that contained a fluorophore. We assessed whether M-SPIO labeling obtained without the use of a transfection agent induced any cell damage in clinical-grade hMSCs and whether it may be useful for in vivo MRI studies after stroke. M-SPIOs provided efficient intracellular hMSC labeling and did not modify cell viability, phenotype, or in vitro differentiation capacity. Following grafting in a rat model of stroke, labeled hMSCs could be detected using both in vivo MRI and fluorescent microscopy until 4 weeks following transplantation. However, whereas good label stability and unaffected hMSC viability were observed in vitro, grafted hMSCs may die and release iron particles in vivo.
Concise Review: Adipose-Derived Stromal Vascular Fraction Cells and Platelet-Rich Plasma: Basic and Clinical Implications for Tissue Engineering Therapies in Regenerative Surgery
Authors: Gentile Pietro , Orlandi Augusto , Scioli Maria Giovanna , Di Pasquali Camilla , Bocchini Ilaria , Cervelli Valerio 
Published: May 2012

AbstractCell-based therapy and regenerative medicine offer a paradigm shift in regard to various diseases causing loss of substance or volume and tissue or organ damage. Recently, many authors have focused their attention on mesenchymal stem cells for their capacity to differentiate into many cell lineages. The most widely studied types are bone marrow mesenchymal stem cells and adipose-derived stem cells (ADSCs), which display similar results. Based on the literature, we believe that the ADSCs offer advantages because of lower morbidity during the harvesting procedure. Additionally, platelet-rich plasma can be used in this field for its ability to stimulate tissue regeneration. The aims of this article are to describe ADSC preparation and isolation procedures, preparation of platelet-rich plasma, and the application of ADSCs in regenerative plastic surgery. We also discuss the mechanisms and future role of ADSCs in cell-based therapy and tissue engineering.
Generation of Retinal Pigment Epithelial Cells from Small Molecules and OCT4 Reprogrammed Human Induced Pluripotent Stem Cells
Authors: Krohne Tim U. , Westenskow Peter D. , Kurihara Toshihide , Friedlander David F. , Lehmann Mandy , Dorsey Alison L. , Li Wenlin , Zhu Saiyong , Schultz Andrew , Wang Junhua , Siuzdak Gary , Ding Sheng , Friedlander Martin 
Published: May 2012

Abstract
Autologous retinal pigment epithelium (RPE) grafts derived from induced pluripotent stem cells (iPSCs) may be used to cure blinding diseases in which RPE dysfunction results in photoreceptor degeneration. Four-, two-, and one-factor-derived iPSCs (4F-, 2F-, and 1F-iPSCs, respectively) were differentiated into fully functional cuboidal pigmented cells in polarized monolayers that express RPE-specific markers. 1F-iPSC-RPE (1F-iPS-RPE) strongly resembles primary human fetal RPE (hfRPE) based on proteomic and untargeted metabolomic analyses, and using novel in vivo imaging technology coupled with electroretinography, we demonstrated that 1F-iPS-RPE mediate anatomical and functional rescue of photoreceptors after transplantation in an animal model of RPE-mediated retinal degeneration. 1F-iPS-RPE cells were injected subretinally as a suspension and formed a monolayer dispersed between host RPE cells. Furthermore, 1F-iPS-RPE do not simply provide trophic support to rescue photoreceptors as previously speculated but actually phagocytose photoreceptor outer segments in vivo and maintain visual cycling. Thus, 1F-iPS-RPE grafts may be superior to conventional iPS-RPE for clinical use because 1F-iPS-RPE closely resemble hfRPE, mediate anatomical and functional photoreceptor rescue in vivo, and are generated using a reduced number of potentially oncogenic reprogramming factors.