# The Clinical Trials of Mesenchymal Stromal Cells Therapy

Authors: Mohammad Reza Kouchakian; Neda Baghban; Seyedeh Farzaneh Moniri; Mandana Baghban; Shabnam Bakhshalizadeh; Vahid Najafzadeh; Zahra Safaei; Safoura Izanlou; Arezoo Khoradmehr; Iraj Nabipour; Reza Shirazi; Amin Tamadon
Journal: Stem Cells International
 (2021)

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## Abstract

Mesenchymal stromal cells (MSCs) are a heterogeneous population of adult stem cells, which are multipotent and possess the ability to differentiate/transdifferentiate into mesodermal and nonmesodermal cell lineages. MSCs display broad immunomodulatory properties since they are capable of secreting growth factors and chemotactic cytokines. Safety, accessibility, and isolation from patients without ethical concern make MSCs valuable sources for cell therapy approaches in autoimmune, inflammatory, and degenerative diseases. Many studies have been conducted on the application of MSCs as a new therapy, but it seems that a low percentage of them is related to clinical trials, especially completed clinical trials. Considering the importance of clinical trials to develop this type of therapy as a new treatment, the current paper is aimed at describing characteristics of MSCs and reviewing relevant clinical studies registered on the NIH database during 2016-2020 to discuss recent advances on MSC-based therapeutic approaches being used in different diseases.


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## Body

## 1. Introduction

In general, stem cells refer to a population of undifferentiated cells that are potent for proliferation, differentiation, and self-renewal [1]. With regard to potency, stem cells belong to one of four types including unipotent, multipotent, pluripotent, and totipotent cells [2]. Stem cells are defined as unipotent if they maintain the ability to just self-renew and can only differentiate into cell types of a single tissue layer. Stem cells are defined as multipotent if they differentiate into several different cell types within a single germ layer. If they differentiate into cell types from all three germ layers, namely, ectoderm, mesoderm, endoderm, and functional gametes, they are called pluripotent stem cells [3]. Totipotent stem cells can form all cell types of the adult organism as well as extraembryonic tissues [4, 5]. Based on the origin of the tissue, stem cells are also categorized to embryonic and adult. A new type of stem cells called induced pluripotent stem cells (iPSCs) has been introduced in recent years [6]. Embryonic stem cells (ESCs), which are derived from the inner cell mass of the preimplantation blastocysts are defined as pluripotent stem cells [7, 8]. Adult stem cells are present in adult tissues and replenish senescent cells and subsequently regenerate damaged tissues. These cells, including mainly hematopoietic, neural crest-derived, and mesenchymal stromal/stem cells (MSCs), are also known as multipotent stem cells [9–12].The aforementioned features of stem cells extensively have attracted attention of experts in stem cell biology, developmental biology, biomaterial sciences, tissue engineering, and other relevant fields for restoring damaged cells and tissues to a condition as close to its normal structure and function as possible. In other words, stem cells have developed a new and surprising scenario in regenerative medicine. Nowadays, stem cell therapy not only stands at the forefront of tissue engineering and regenerative medicine but also is increasingly developed in other medical fields such as gene and drug delivery systems [13, 14]. According to the U. S. National Library of Medicine (https://clinicaltrials.gov), a total number of 6205 clinical trials on stem cell therapy worldwide were registered till 5/18/2021. Between them, 1240 of which are related to MSC therapy.ESCs and MSCs have a number of advantages and disadvantages in their use [15–17]. The reason for this greater tendency to MSCs than other stem cell types can be understood by comparing the advantages and disadvantages of them. Strauer and Kornowski note ESCs as highly expandable and pluripotent but limited by risk of rejection, difficult isolation, risk of malignancy, and ethical objection. They contrast that MSCs are easily obtained, expanded, compatible, and are socially acceptable [15].Following the discovery of novel treatments for diseases in laboratory and animal models, clinical trials are essential to find treatments that work properly in humans. As abovementioned, the interest of scientists to the MSC-based therapy has increased in recent years. Therefore, the current review paper is aimed at describing characteristics of MSCs and the recent advances on MSC-based therapy.


## 2. Method

This review is aimed at answering the questions “Which characteristics of MSC has attracted the attention of scientists to apply it as a therapy?”, “How many clinical trials have been reported on the NIH database over a 5-year period of 2016-2020 and how many of them are related to completed and active trials?”, and “For which diseases have no MSC-based therapy clinical trials been reported?”. The clinical trials of MSC therapy were searched through the U. S. National Library of Medicine (https://clinicaltrials.gov) using keywords of “mesenchymal + therapy.” The period of trials was limited to 2016-2020. The result of the search showed 1240 trials. The criteria for selecting articles were their status. The completed, active, and recruiting trials were selected. Accordingly, 290 of which were selected to summarize their available data in Tables 1–3. Data summarized in Table 4 were obtained by searching key words of “mesenchymal+ therapy” and omitting diseases listed in Tables 1–3 through the PubMed database. The purpose of presenting Table 4 was to find conditions that have been treated in preclinical experiments with MSCs but are yet to be translated into clinical trials.Table 1
Completed clinical trials on mesenchymal stromal cell-based therapy during 2016-2020 (U. S. National Library of Medicine).
Organ systemDisease/syndromePhaseDateCountrySourceTransplantationCT codeCardiovascularCardiomyopathy12019United StatesNDAllotransplantNCT02509156CardiovascularGraft versus host disease1 and 22016PakistanBone marrowAllotransplantNCT02824653CardiovascularIschemic cardiomyopathy22020United StatesBone marrowAutotransplantNCT02501811GastrointestinalCirrhosis42020IndiaBone marrowAutotransplantNCT04243681GastrointestinalXerostomia22017DenmarkAdipose tissueAutotransplantNCT02513238GastrointestinalType 2 diabetes mellitus1 and 22019VietnamBone marrowAutotransplantNCT03343782ImmuneDiscordant immunological response in HIV1 and 22019SpainAdipose tissueAllotransplantNCT02290041ImmuneSystemic lupus erythematosus12018United StatesUmbilical cordAllotransplantNCT03171194IntegumentaryAtopic dermatitis12017KoreaNDAutotransplantNCT02888704IntegumentaryCaesarean section scars22018ChinaUmbilical cordAllotransplantNCT02772289IntegumentaryChronic ulcer12020IndonesiaConditioned mediumWharton’s jellyAllotransplantNCT04134676IntegumentaryChronic venous ulcer1 and 22020GermanySkinAllotransplantNCT03257098IntegumentaryDiabetic foot ulcer22016KoreaAdipose tissueAllotransplantNCT02619877IntegumentaryDiabetic neuropathic ulcer1 and 22020GermanySkinAllotransplantNCT03267784IntegumentaryGingival recession1 and 22019BelarusAdipose tissueAutotransplantNCT04434794IntegumentaryPerianal fistula12019United StatesNDAutotransplantNCT02589119IntegumentaryRecessive dystrophic epidermolysis bullosa1 and 22020KoreaUmbilical cordAllotransplantNCT04520022IntegumentaryRectovaginal fistula12019RussiaAdipose tissueAutotransplantNCT03643614IntegumentarySkin scar1 and 22019PolandAdipose tissueAutotransplantNCT03887208IntegumentarySkin wound12019PakistanUmbilical cordAllotransplantNCT04219657IntegumentarySurgical leak fistula12019United StatesAdipose tissueAutotransplantNCT02807389IntegumentaryUltrafiltration failure1 and 22017IranAdipose tissueAllotransplantNCT02801890NervousAlzheimer’s disease1 and22019United StatesAdipose tissueAutotransplantNCT03117738NervousBrain death12020IndiaNDNDNCT02742857NervousCerebral infarction1 and 22017KoreaUmbilical cordAllotransplantNCT02378974NervousCorneal ulcerCorneal diseaseCorneal dystrophy1&22019BelarusAdipose tissueAutotransplantNCT04484402NervousMotor neuron disease12016BrazilNDAutotransplantNCT02987413NervousMultiple sclerosis22019CanadaNDAutotransplantNCT02239393NervousMultiple sclerosis1 and 22020JordanUmbilical cordAllotransplantNCT03326505NervousMultiple sclerosis22018IsraelBone marrowAutotransplantNCT02166021NervousMultiple sclerosis1 and22017SpainBone marrowAutotransplantNCT02495766NervousOcular corneal burn22017ChinaBone marrowNDNCT02325843NervousParkinson’s disease12019United StatesBone marrowAutotransplantNCT02611167NervousRefractory epilepsy12019RussiaAdipose tissueAutotransplantNCT03676569NervousRetinitis pigmentosa32019TurkeyWharton’s jellyAllotransplantNCT04224207NervousSpinal cord injuries1 and 22018JordanBone marrowAdipose tissueAutotransplantNCT02981576NervousSpinal cord injuries1 and 22020ChinaUmbilical cordAllotransplantNCT02481440NervousSpinal cord injuries22017SpainBone marrowAutotransplantNCT02570932NervousSpinal cord injury1 and 22019SpainWharton’s jellyAllotransplantNCT03003364ReproductiveAtrophic endometrium22019RussiaBone marrowAutotransplantNCT03166189ReproductiveErectile dysfunction12018KoreaBone marrowAutotransplantNCT02344849ReproductiveErectile dysfunction12018JordanWharton’s jellyAllotransplantNCT02945449ReproductiveErectile dysfunction1 and 22019JordanWharton’s jellyAllotransplantNCT03751735ReproductiveFistula vagina12020United StatesNDAutotransplantNCT03220243ReproductiveOvarian cancer12019United StatesNDAutotransplantNCT02530047ReproductivePremature ovarian failure1 and 22018ChinaUmbilical cordAllotransplantNCT02644447RespiratoryAcute respiratory distress syndrome12019United StatesBone marrowAllotransplantNCT02804945RespiratoryBronchopulmonary dysplasia1 and 22016United StatesUmbilical cordAllotransplantNCT02381366RespiratoryCOVID-19Acute respiratory distress syndrome1 and 22020United StatesUmbilical cordAllotransplantNCT04355728RespiratoryCOVID-19Prophylaxis12020United StatesUmbilical cordAllotransplantNCT04573270RespiratoryCOVID-1922020ChinaUmbilical cordAllotransplantNCT04288102RespiratoryCOVID-1912020ChinaExosomeAdipose tissueAllotransplantNCT04276987RespiratoryLaryngotracheal stenosis1 and 22019BelarusOlfactory mucosaAutotransplantNCT03130374RespiratoryNoncystic fibrosis bronchiectasis12019United StatesBone marrowAllotransplantNCT02625246RespiratoryPneumoconiosis12019ChinaUmbilical cordAllotransplantNCT02668068SkeletalBone fracture1 and 22020IndiaAdipose tissueAutotransplantNCT04340284SkeletalDental implant therapy1 and 22017GreeceBone marrowAutotransplantNCT03070275SkeletalKnee osteoarthritis22018United StatesBone marrowAutotransplantNCT02958267SkeletalKnee osteoarthritis1 and 22018CanadaBone marrowAutotransplantNCT02351011SkeletalKnee osteoarthritis22018United StatesAdipose tissueAutotransplantNCT02674399SkeletalOsteoarthritis12018ChinaAdipose tissueAllotransplantNCT02641860SkeletalOsteonecrosis1 and 22018SpainBone marrowAutotransplantNCT01605383SkeletalOsteoporosisSpinal fractures12016SpainBone marrowAutotransplantNCT02566655SkeletalRheumatoid arthritis12018IranBone marrowAutotransplantNCT03333681SkeletalRheumatoid arthritis1 and 22020United StatesAdipose tissueAutotransplantNCT03691909UrinaryStress urinary incontinence1 and 22019BelarusAdipose tissueAutotransplantNCT04446884UrinaryStress urinary incontinence32016EgyptBone marrowAutotransplantNCT02334878ND: no data.Table 2
Active clinical trials on mesenchymal stromal/stem cell-based therapy started during 2016-2020 (U. S. National Library of Medicine).
Organ systemDisease/syndromePhaseDateCountrySourceTransplantationCT codeCardiovascularHypoplastic left heart syndrome1 and 22018United StatesBone marrowAllotransplantNCT03525418GastrointestinalCystic fibrosis12016United StatesBone marrowAllotransplantNCT02866721GastrointestinalDiabetes1 and 22017United StatesNDAllotransplantNCT02886884GastrointestinalInflammatory bowel1 and 22017JordanWharton’s jellyAllotransplantNCT03299413GastrointestinalPrimary sclerosing cholangitis1 and 22017ChinaUmbilical cordAllotransplantNCT03516006GastrointestinalXerostomia12019DenmarkAdipose tissueAllotransplantNCT03874572ImmuneGraft versus host disease1 and 22016SpainAdipose tissueAutotransplantNCT02687646ImmuneGraft versus host disease12018United StatesUmbilical cordWharton’s jellyAllotransplantNCT03158896IntegumentaryEpidermolysis bullosa1 and 22018SpainBone marrowAllotransplantNCT04153630IntegumentaryEpidermolysis bullosa1 and 22019United KingdomSkinAllotransplantNCT03529877IntegumentaryInflammation1 and 22018United StatesBone marrowAllotransplantNCT03059355IntegumentaryPsoriasis1 and 22017ChinaAdipose tissueAllotransplantNCT03265613NervousAlcoholism1 and 22018United StatesNDAllotransplantNCT03265808NervousAlzheimer’s disease1 and 22020United StatesAdipose tissueAutotransplantNCT04228666NervousAlzheimer’s disease12016United StatesBone marrowAllotransplantNCT02600130NervousAmyotrophic lateral sclerosis32017United StatesUmbilical cordAllotransplantNCT03280056NervousCerebral palsy1 and 22016JordanBone marrowAutotransplantNCT03078621NervousCerebral palsy22017IranUmbilical cordAllotransplantNCT03795974NervousCerebral palsy1 and 22018United StatesUmbilical cordAllotransplantNCT03473301NervousHuntington disease22018BrazilDental pulpAllotransplantNCT03252535NervousHuntington disease12017BrazilDental pulpAllotransplantNCT02728115NervousMultiple sclerosis22018United StatesBone marrowAutotransplantNCT03355365NervousMultiple sclerosis22019United StatesNDAutotransplantNCT03799718NervousMultiple system atrophy12018KoreaBone marrowAutotransplantNCT04495582NervousNervous injury1 and 22017ChinaUmbilical cordAllotransplantNCT03291366NervousParkinson’s disease22017BelarusBone marrowAutotransplantNCT04146519NervousSpinal cord injury12017United StatesAdipose tissueAutotransplantNCT03308565RespiratoryCOVID-191 and 22020SpainAdipose tissueAllotransplantNCT04366323RespiratoryCOVID-1922020United StatesAdipose tissueAllotransplantNCT04362189RespiratoryCOVID-1922020United StatesAdipose tissueAutotransplantNCT04349631RespiratoryCOVID-191 and 22020FranceUmbilical cordWharton’s jellyAllotransplantNCT04333368SkeletalKnee osteoarthritis12019United StatesAdipose tissueAutotransplantNCT04043819SkeletalLateral epicondylitis22018KoreaAdipose tissueAllotransplantNCT03449082SkeletalOsteoarthritis22017KoreaAdipose tissueAutotransplantNCT03509025SkeletalOsteoarthritis32019KoreaAdipose tissueAutotransplantNCT03990805SkeletalOsteoarthritis12016JordanBone marrowAutotransplantNCT03067870UrinaryFistula12017United StatesAdipose tissueAutotransplantNCT02808208UrinaryKidney injury1 and 22017United StatesBone marrowAllotransplantNCT03015623UrinaryNephrosis22016ChinaBone marrowAutotransplantNCT02966717ND: no data.Table 3
Recruiting clinical trials on mesenchymal stromal/stem cell-based therapy started during 2016-2020 (U. S. National Library of Medicine).
Organ systemDisease/syndromePhaseDateCountrySourceTransplantationCT codeCardiovascularAbdominal aortic aneurysm12016United StatesNDAllotransplantNCT02846883CardiovascularAcute myocardial infarction1 and 22019IndonesiaUmbilical cordAllotransplantNCT04340609CardiovascularAcute myocardial infarction12019TaiwanUmbilical cordAllotransplantNCT04056819CardiovascularCardiomyopathy12020United StatesBone marrowAllotransplantNCT02962661CardiovascularCerebrovascular disorders1 and 22019IranExosomeAllotransplantNCT03384433CardiovascularCritical limb ischemia12020KoreaAdipose tissueAllotransplantNCT04661644CardiovascularCritical limb ischemia22020FranceAdipose tissueAutotransplantNCT03968198CardiovascularDiabetic foot ulcer32020KoreaAdipose tissueAllotransplantNCT04569409CardiovascularDiabetic foot ulcer12020ChinaUmbilical cordAllotransplantNCT04464213CardiovascularHeart defects1 and 22017United StatesNDAllotransplantNCT03079401CardiovascularHeart failure12016United StatesBone marrowAllotransplantNCT02408432CardiovascularHeart failure2 and 32018PolandWharton’s jellyAllotransplantNCT03418233CardiovascularIschemia12017United StatesBone marrowAllotransplantNCT02685098CardiovascularIschemia reperfusion injury22020United StatesAdipose tissueAllotransplantNCT04388761CardiovascularIschemic heart disease1 and 22018ChinaBone marrowAutotransplantNCT03397095CardiovascularIschemic stroke12020TaiwanUmbilical cordAllotransplantNCT04434768CardiovascularIschemic stroke12019TaiwanUmbilical cordAllotransplantNCT04097652CardiovascularMyocardial infarction12019SpainUmbilical cordAllotransplantNCT03798353CardiovascularMyocardial infarction2 and 32017PolandWharton’s jellyAllotransplantNCT03404063CardiovascularMyocardial ischemia22016FranceBone marrowAutotransplantNCT02462330DigestiveCrohn colitis1 and 22020United StatesBone marrowAllotransplantNCT04548583DigestiveCrohn disease12018United StatesNDAutotransplantNCT03449069DigestiveCrohn disease1 and 22018BelgiumNDNDNCT03901235DigestiveFistula1 and 22020United StatesBone marrowAllotransplantNCT04519671DigestiveFistula1 and 22020United StatesBone marrowAllotransplantNCT04519684DigestiveHepatitis B12018ChinaUmbilical cordAllotransplantNCT03826433DigestiveLiver cirrhosis1 and 22018SingaporeBone marrowAutotransplantNCT03626090DigestiveLiver cirrhosis22019ChinaUmbilical cordAllotransplantNCT03945487DigestiveLiver cirrhosis1 and 22018IndonesiaUmbilical cordAllotransplantNCT04357600DigestiveLiver failure1 and 22019GermanySkinAllotransplantNCT03860155DigestiveLiver transplantation12017GermanyBone marrowAllotransplantNCT02957552DigestivePrimary biliary cirrhosis1 and 22019VietnamUmbilical cordAllotransplantNCT04522869DigestiveRectovaginal fistula1 and 22020United StatesBone marrowAllotransplantNCT04519697DigestiveUlcerative colitis1 and 22018ChinaAdipose tissueAllotransplantNCT03609905DigestiveUlcerative colitis12020United StatesAdipose tissueAutotransplantNCT04312113DigestiveUlcerative colitis1 and 22020United StatesBone marrowAllotransplantNCT04543994EndocrineDiabetic kidney disease12019United StatesAdipose tissueAutotransplantNCT03840343EndocrineType 1 diabetes12017JordanAdipose tissueAllotransplantNCT02940418EndocrineType 1 diabetes1 and 22019SwedenWharton’s jellyAllotransplantNCT03973827EndocrineType 2 diabetes1 and 22016IndonesiaBone marrowUmbilical cordAutotransplantAllotransplantNCT04501341EndocrineType 2 diabetes1 and 22020ChinaUmbilical cordAllotransplantNCT04441658ImmuneAcute graft versus host disease1 and 22019MalaysiaUmbilical cordAllotransplantNCT03847844ImmuneDiabetic foot ulcer12019United StatesUmbilical cordAllotransplantNCT04104451ImmuneDrug resistant1 and 22020ChinaAdipose tissueAllotransplantNCT04544215ImmuneKeratoconjunctivitis sicca22020DenmarkAdipose tissueAllotransplantNCT04615455ImmuneLupus erythematosus1 and 22019BelarusOlfactory mucosaAllotransplantNCT04184258ImmuneLymphoblastic leukemia22017United StatesUmbilical cordAutotransplantNCT03096782ImmunePrimary sclerosing cholangitisAutoimmune hepatitis1 and 22018United KingdomUmbilical cordAllotransplantNCT02997878ImmuneRenal lupus22019ChileUmbilical cordAllotransplantNCT03917797ImmuneType 1 diabetes12020United StatesUmbilical cordAllotransplantNCT04061746ImmuneType 1 diabetes1 and 22017SwedenWharton’s jellyAllotransplantNCT03406585IntegumentaryCaesarean section scars22020ChinaPerinatal tissueAllotransplantNCT04034615IntegumentaryPsoriasis1 and 22019ChinaAdipose tissueAllotransplantNCT03392311IntegumentaryWound12019ChinaNDConditioned mediumNDNCT04235296NervousAlzheimer’s disease1 and 22020ChinaAdipose tissueAllotransplantNCT04388982NervousAlzheimer’s disease12019United StatesUmbilical cordAllotransplantNCT04040348NervousAmyotrophic lateral sclerosis22017United StatesAdipose tissueAutotransplantNCT03268603NervousAmyotrophic lateral sclerosis1 and 22020PolandWharton’s jellyAllotransplantNCT04651855NervousCerebral palsy1 and 22020IndonesiaUmbilical cordAllotransplantNCT04314687NervousCornea12020United StatesBone marrowAllotransplantNCT04626583NervousDry eye1 and 22020ChinaUmbilical cordExosomeAllotransplantNCT04213248NervousNonarteritic anterior ischemic optic neuropathy22018SpainBone marrowAllotransplantNCT03173638NervousParkinson’s disease1 and 22018JordanUmbilical cordAllotransplantNCT03684122NervousParkinson’s disease22020United StatesBone marrowAllotransplantNCT04506073NervousRecurrent glioblastoma12019United StatesBone marrowAllotransplantNCT03896568NervousSclerosis12016JordanBone marrowAutotransplantNCT03069170NervousSpinal cord injuries1 and 22016SpainAdipose tissueAllotransplantNCT02917291NervousSpinal cord injuries22020United StatesAdipose tissueAutotransplantNCT04520373NervousSpinal cord injuries12017JordanBone marrowAutotransplantNCT04288934NervousSpinal cord injuries22019ChinaUmbilical cordAllotransplantNCT03521336NervousSpinal cord injuries22019ChinaUmbilical cordAllotransplantNCT03521323NervousSpinal cord injuries22019ChinaUmbilical cordAllotransplantNCT03505034NervousStroke1 and 22020NetherlandsBone marrowAllotransplantNCT03356821NervousTraumatic brain injury1 and 22020United StatesAdipose tissueAutotransplantNCT04063215ReproductiveErectile dysfunction22020KoreaBone marrowAutotransplantNCT04594850ReproductiveIntraventricular hemorrhage22017KoreaUmbilical cordAllotransplantNCT02890953ReproductiveUterine scar12020ChinaUmbilical cordAllotransplantNCT03181087ReproductiveUterine scar22020ChinaUmbilical cordAllotransplantNCT02968459ReproductiveUterus injury22020ChinaUmbilical cordAllotransplantNCT03386708RespiratoryAcute respiratory distress syndrome1 and 22019SpainAdipose tissueAllotransplantNCT04289194RespiratoryAcute respiratory distress syndrome22019United StatesBone marrowAllotransplantNCT03818854RespiratoryAcute respiratory distress syndrome1 and 22020United StatesNDAllotransplantNCT04524962RespiratoryAcute respiratory distress syndrome1 and 22019United KingdomUmbilical cordAllotransplantNCT03042143RespiratoryAdenocarcinoma of lung1 and 22019United KingdomNDAllotransplantNCT03298763RespiratoryBronchopulmonary dysplasia12019United StatesBone marrowExosomeAllotransplantNCT03857841RespiratoryBronchopulmonary dysplasia12019SpainNDNDNCT02443961RespiratoryBronchopulmonary dysplasia1 and 22019ChinaUmbilical cordAllotransplantNCT03645525RespiratoryBronchopulmonary dysplasia12018ChinaUmbilical cordAllotransplantNCT03873506RespiratoryBronchopulmonary dysplasia1 and 22019ChinaUmbilical cordAllotransplantNCT03774537RespiratoryBronchopulmonary dysplasia12018ChinaUmbilical cordAllotransplantNCT03558334RespiratoryBronchopulmonary dysplasia22018KoreaUmbilical cordAllotransplantNCT03392467RespiratoryBronchopulmonary dysplasia22019KoreaUmbilical cordAllotransplantNCT04003857RespiratoryBronchopulmonary dysplasia12018TaiwanUmbilical cordAllotransplantNCT03631420RespiratoryBronchopulmonary dysplasia12019VietnamUmbilical cordAllotransplantNCT04062136RespiratoryChronic lung allograft dysfunction22017AustraliaBone marrowAllotransplantNCT02709343RespiratoryChronic obstructive pulmonary disease12020United StatesNDNDNCT04047810RespiratoryChronic obstructive pulmonary disease1 and 22020VietnamUmbilical cordAllotransplantNCT04433104RespiratoryChronic obstructive pulmonary disease12020TaiwanUmbilical cordAllotransplantNCT04206007RespiratoryCOVID-1912020MexicoAdipose tissueAllotransplantNCT04611256RespiratoryCOVID-191 and 22020BelgiumBone marrowAllotransplantNCT04445454RespiratoryCOVID-1912020CanadaBone marrowAllotransplantNCT04400032RespiratoryCOVID-1922020PakistanBone marrowAllotransplantNCT04444271RespiratoryCOVID-1922020SpainBone marrowAllotransplantNCT04361942RespiratoryCOVID-1912020SwedenBone marrowAllotransplantNCT04447833RespiratoryCOVID-1912020United StatesBone marrowAllotransplantNCT04397796RespiratoryCOVID-1932020United StatesBone marrowAllotransplantNCT04371393RespiratoryCOVID-1912020United StatesBone marrowAllotransplantNCT04629105RespiratoryCOVID-1912020United StatesCord bloodAllotransplantNCT04565665RespiratoryCOVID-191 and 22020United StatesWharton’s jellyAllotransplantNCT04399889RespiratoryCOVID-191 and 22020ChinaDental pulpAllotransplantNCT04336254RespiratoryCOVID-1912020IndonesiaNDAllotransplantNCT04535856RespiratoryCOVID-1922020MexicoNDAllotransplantNCT04416139RespiratoryCOVID-1922020SpainNDAllotransplantNCT04615429RespiratoryCOVID-1922020United StatesNDAllotransplantNCT04466098RespiratoryCOVID-1912020BrazilNDAllotransplantNCT04525378RespiratoryCOVID-192 and 32020IranNDExosomeNDNCT04366063RespiratoryCOVID-191 and 22020United StatesNDAllotransplantNCT04524962RespiratoryCOVID-191 and 22020UkraineUmbilical cordAllotransplantNCT04461925RespiratoryCOVID-1922020GermanyIsraelUmbilical cordAllotransplantNCT04614025RespiratoryCOVID-1922020United StatesUmbilical cordAllotransplantNCT04389450RespiratoryCOVID-191 and 22020ChinaUmbilical cordAllotransplantNCT04339660RespiratoryCOVID-1912020IndonesiaUmbilical cordAllotransplantNCT04457609RespiratoryCOVID-1922020SpainUmbilical cordAllotransplantNCT04366271RespiratoryCOVID-191 and 22020United StatesUmbilical cordAllotransplantNCT04494386RespiratoryCOVID-1922020PakistanUmbilical cordAllotransplantNCT04437823RespiratoryCOVID-1912020ChinaUmbilical cordAllotransplantNCT04252118RespiratoryCOVID-191 and 22020TurkeyUmbilical cordAllotransplantNCT04392778RespiratoryCOVID-1912020JordanWharton’s jellyAllotransplantNCT04313322RespiratoryCOVID-191 and 22020SpainWharton’s jellyAllotransplantNCT04390139RespiratoryHealthy12020ChinaAdipose tissue exosomeAllotransplantNCT04313647RespiratoryHoarseness1 and 22020SwedenBone marrowAutotransplantNCT04290182RespiratoryLung disease12019United StatesBone marrowAllotransplantNCT03929120RespiratoryPneumonia22020ChinaUmbilical cordAllotransplantNCT04269525RespiratoryPulmonary hypertension1 and 22019ChinaAdipose tissueAutotransplantNCT04055415SkeletalAlveolar bone atrophy32020SpainBone marrowAutotransplantNCT04297813SkeletalAneurysmal bone cyst1 and 22018JordanBone marrowAutotransplantNCT03066245SkeletalCartilage defect12018United StatesAdipose tissueAutotransplantAllotransplantNCT03672825SkeletalDisc disease22017IndonesiaBone marrowAllotransplantNCT04499105SkeletalDisc disease12019ChinaUmbilical cordAllotransplantNCT04104412SkeletalKnee cartilage injury1 and 22018ChinaAdipose tissueAutotransplantNCT03955497SkeletalKnee osteoarthritis22020ChinaAdipose tissueAllotransplantNCT04208646SkeletalKnee osteoarthritis1 and 22019TaiwanAdipose tissueAllotransplantNCT03943576SkeletalKnee osteoarthritis1 and 22019PolandAdipose tissueAutotransplantNCT03869229SkeletalKnee osteoarthritis12017JordanAdipose tissueAutotransplantNCT02966951SkeletalKnee osteoarthritis1 and 22020UkraineBone marrowAllotransplantNCT04453111SkeletalKnee osteoarthritis1 and 22019KoreaBone marrowAllotransplantNCT04240873SkeletalKnee osteoarthritis12018United StatesBone marrowAutotransplantNCT03477942SkeletalKnee osteoarthritis12019ChileUmbilical cordAllotransplantNCT03810521SkeletalKnee osteoarthritis12019KoreaUmbilical cordAllotransplantNCT04037345SkeletalKnee osteoarthritis12020KoreaUmbilical cordAllotransplantNCT04339504SkeletalKnee osteoarthritis12017JordanWharton’s jellyAllotransplantNCT02963727SkeletalLow back pain12020United StatesBone marrowAllotransplantNCT04410731SkeletalMeniscus injuries22019United StatesAdipose tissueAutotransplantNCT04274543SkeletalNonunion fracture32017FranceGermanyBone marrowAutotransplantNCT03325504SkeletalOsteoarthritis22016FranceAdipose tissueAutotransplantNCT02838069SkeletalOsteoarthritis12016United StatesAdipose tissueAutotransplantNCT02805855SkeletalOsteoarthritis12018United StatesAdipose tissueAutotransplantNCT03608579SkeletalOsteoarthritis32019United StatesBone marrowAdipose tissueAutotransplantNCT03818737SkeletalOsteoarthritis22020ChinaUmbilical cordAllotransplantNCT03383081SkeletalOsteoarthritis1 and 22020IndonesiaUmbilical cordAllotransplantNCT04314661SkeletalOsteoarthritis1 and 22019PolandWharton’s jellyAllotransplantNCT03866330SkeletalOsteochondral fracture of talus32019ChileUmbilical cordAllotransplantNCT03905824SkeletalOsteogenesis imperfecta1 and 22019SwedenFetal liverAllotransplantNCT03706482SkeletalOsteoporosis22020IndonesiaUmbilical cordAllotransplantNCT04501354SkeletalRheumatoid arthritis12017United StatesNDAllotransplantNCT03186417SkeletalRheumatoid arthritis1 and 22018KoreaUmbilical cordAllotransplantNCT03618784SkeletalRotator cuff tear22020BrazilNDNDNCT03362424SkeletalSpinal tuberculosis22017IndonesiaNDNDNCT04493918UrinaryCOVID-191 and 22020United StatesBone marrowAllotransplantNCT04445220UrinaryKidney diseases1 and 22019BangladeshAdipose tissueAutotransplantNCT03939741UrinaryKidney diseases1 and 22017IrelandItalyUnited KingdomBone marrowAllotransplantNCT02585622UrinaryNephropathy12020JapanAdipose tissueAllotransplantNCT04342325UrinaryPelvic radiation22019FranceNDNDNCT02814864UrinaryRenal12020United StatesAdipose tissueAllotransplantNCT04392206UrinaryRenal transplantation12018United StatesNDAllotransplantNCT03504241UrinaryRenal transplantation22016United StatesNDAutotransplantNCT03478215UrinaryType 2 diabetes1 and 22020ChinaUmbilical cordAllotransplantNCT04216849ND: no data.Table 4
Diseases can be tested clinically for treatment with mesenchymal stromal/stem cells in human based on the successfulin vivo model studies.
Organ systemDisease/syndromeSourceTransplantationReferencesCardiovascularMyelodysplastic syndromesBone marrowAllotransplant[114]GastrointestinalHepatic failureBone marrowAllotransplant[115]NervousEpilepticusExosomeAllotransplant[117]NervousGlioblastomaBone marrowAllotransplant[118]NervousGlioblastomaAdipose tissueAllotransplant[119]NervousHypoxic-ischemic encephalopathyUmbilical cordAllotransplant[120]NervousLoss of retinal ganglion cellsBone marrow-derived exosomesAllotransplant[121]NervousNerve regenerationBone marrowAllotransplant[122]ReproductiveAzoospermiaAdipose tissueAllotransplant[123]ReproductiveAzoospermiaBone marrowAllotransplant[124]ReproductiveMammary adenocarcinomaAdipose tissueAllotransplant[116]SkeletalBone formationNDAllotransplant[125]SkeletalCalvarial defectsBone marrowAdipose tissueAllotransplant[126]SkeletalPeriodontal defectsExosomeAllotransplant[127]UrinaryFocal segmental glomerulosclerosisBone marrowAllotransplant[128]UrinaryNephron generation in kidney corticesNDAllotransplant[129]ND: no data.


## 3. MSCs

Friedenstein et al. first described MSCs as a population of fibroblast-like cells in the bone marrow [18]. According to the International Society for Cellular Therapy (ISCT) definition, to be classified as MSCs, the cells must satisfy four minimal criteria: (i) specific surface antigen expression (>95%) including CD73, CD90, CD105, CD44, CD71, Stro-1, CD106, CD166, CD29, and ICAM-1, (ii) do not express hematopoietic markers (CD45, CD34, CD14, and CD11), endothelial (CD31), and costimulatory markers (CD80, CD86), (iii) adherence to the plastic plate surface, and (iv) capability to differentiate into osteogenic, adipogenic, and chondrogenic lineages [19].Some studies have demonstrated that MSCs are able to transdifferentiate into nonmesenchymal cells (hepatic, renal, cardiac, neural, and Schwann cells) [20–25]. These cells express pluripotency-associated factors including OCT-4, SOX-2, and NANOG [26]. However, their expression depends on the type of MSCs and their niche [27]. The niche of MSCs is the subject of much debate and has not been fully understood yet. Nonetheless, three factors may play a critical role in the residing of MSCs: (i) expression of the receptors and adhesion molecules in MSCs [28], (ii) interaction with endothelial cells [29], and (iii) expression of signalling molecules from injured tissue [30]. However, factors such as delivery method, the age of MSCs, passage number, the population of MSCs, and the source and culture condition of MSCs can alter their residing efficacy [31].


## 4. Cell Sources of MSCs

MSCs can be easily isolated from several tissues and can be effectively culturedin vitro. As the major sources of MSCs in clinic trials are umbilical cord, bone marrow, and adipose tissues, MSCs derived from these tissues are discussed below (Figure 1). Adult bone marrow-derived MSCs (BM-MSCs) comprise only 0.01% to 0.001% of the bone marrow cell population and can be isolated from osseous biopsies [32, 33]. BM-MSCs are multipotent and capable of differentiating into mesodermal, ectodermal, and endodermal cell lineages. Previous studies have reported that BM-MSCs are a potential source of stem cells with capability in differentiation into male germ cells [34]. It is also shown that these possess high proliferation rate and their immunomodulatory properties act through paracrine mechanisms [35–39]. Accordingly, BM-MSCs can be useful for solving some genetic and immunological problems as well as repairing damaged tissues [40]. Moreover, it has been proved that BM-MSCs secrete cytokines and growth factors and can facilitate engraftment in organs [41–43]. Adipose tissues can be considered as a suitable source for MSCs, as its harvesting is relatively noninvasive. Adipose tissue-derived stem cells (AT-MSCs) can be extracted by liposuction and isolated from the stromal vascular fraction of homogenized adipose tissues [44, 45]. These cells were first identified as MSCs by Zuk and colleagues in 2001 [46]. AT-MSCs can be isolated in high numbers, because of their abundance in the human body [47]. They express MSC markers (CD90, CD44, CD29, CD105, CD13, CD34, CD73, CD166, CD10, CD49e, and CD59) while hematopoietic and endothelial markers (CD31, CD45, CD14, CD11b, CD34, CD19, CD56, and CD146) are downregulated in this cell population [48]. More genetic and morphologic stability in long-term cultures, higher proliferation, and other characteristics give AT-MSCs a distinct advantage over BM-MSCs [49, 50]. However, their proliferation rate depends on various factors such as donor’s age, fat tissue type (white or brown), location of the harvest (subcutaneous or visceral), culture conditions, cell culture density, and media formulation [51]. The human umbilical cord is a conduit between the developing embryo/fetus and the placenta. It contains two arteries and a vein surrounded by mucosa connective tissue called Wharton’s jelly [52]. The umbilical cord has five various compartments including amniotic epithelium membrane, cord lining, intervascular Wharton’s jelly, and perivascular and mixed cord. There is also a population of stem cells called umbilical cord-derived MSCs (UC-MSCs) that can be isolated from the umbilical cord. Human UC-MSCs draw attention since they are derived from a noncontroversial source, and there are no ethical concerns in harvesting and using them for treatment purposes. Human UC-MSCs are more potent possessing more proliferation potential and differentiation capacity compared to adult tissue-derived MSCs. MSCs population in Wharton’s jelly is higher than the other parts of the umbilical cord [53]. In 1991, McElreavey et al. [54] isolated fibroblast-like cells from Wharton’s jelly of the human umbilical cord for the first time. Wharton’s jelly-derived MSCs (WJ-MSCs) express high level of MSC markers as well as some pluripotency markers [55].Figure 1
Frequency of mesenchymal stromal/stem cell (MSC) source contributions in clinical trials on MSC therapy during 2016-2020 (U. S. National Library of Medicine).


## 5. Therapeutic Application of MSCs

Different types of MSC-based therapy have been studied and discussed for treating of a wide range of diseases such as graft-versus-host-disease [56–58], Crohn’s disease [59, 60], type 1 diabetes [61, 62], multiple sclerosis (MS) [63, 64], lupus [65, 66], cardiovascular diseases [67, 68], liver disorders [69], respiratory disorders [70, 71], spinal cord injury [72, 73], kidney failure [74, 75], skin diseases [76, 77], Alzheimer’s disease [78], and Parkinson disease [79].


## 6. Therapeutic Mechanisms of MSCs

Diverse therapeutic mechanisms have been suggested for MSCs. Exploring these mechanisms are essential to help scientist to select the suitable dosage, administration route, and best engraftment time of MSCs [85]. Several mechanisms can be involved in the therapeutic effects of MSCs on a specific disease, as described below.The therapeutic potential of MSCs can be attributed to their secretory and immunomodulatory properties. Immunomodulatory responses are dependent on the cell-to-cell interaction mechanisms and releasing secretory factors [80, 81]. MSCs secrete a wide range of bioactive molecules including growth and antiapoptotic factors including VEGF, HGF, IGF-1, TGF-β, bFGF, and stanniocalcin-1 [82]. MSC-derived secretory factors induce cell proliferation and angiogenesis and limit the injury site. When the tissue is injured, molecules such as IL-1, IL-2, IL-12, TNF-α, and INF-γ produce inflammatory responses at the injury site [83]. This response prevents the regenerating process by progenitor stem cells [83]. The secretion of PGE-2, iNOS, iDO, HLA-G5, and LIF from MSCs leads to reduced inflammation and subsequent regulation of immune system cells’ function [84].Homing is a feature of MSCs referring to their tendency to home to injured tissues. This ability in MSCs, which was first identified by Saito et al. [86], is effective in treating diseases. Moreover, homing of MSCs to damaged tissues following transplantation suggests them as very promising drug carriers. MSC homing can be affected by several factors including the transplantation time and quantity, pretreatment, the method of culture, and the transplantation approach of MSCs [87, 88].Another possible therapeutic mechanism is the differentiation of MSCs. As above-mentioned, these cells have the ability to differentiate into different cells such as adipocytes, chondrocytes, osteoblasts, myoblasts, and neuron-like cells. This ability has resulted in successful application of MSCs in tissue and scaffold engineering [89–91].Producing trophic factor is another mechanism, as MSCs have ability to play a role as a pool of trophic factor. Following the homing MSCs in injured areas, local stimuli simulate MSCs to secrete growth factors, which have a role in tissue regeneration, angiogenesis, and preventing cell apoptosis [92–94].


## 7. Approaches for Applying MSCs

In general, eight administration methods have been proposed for applying MSCs. These methods include intravenous injection (IV) [95, 96], intra-arterial injection (IA) [97, 98], intrathecal injection (IT) [99, 100], intracardiac injection (IC) [101], intra-articular injection (IAT) [102, 103], intramuscular injection (IM) [104], intraosseous injection (IO) [105], and implant for cells incorporated into a matrix or an implanted device [106, 107]. According to the study on the clinical trials of MSCs over 2014-2018, the most common administration method used in clinical trials was IV. The next common methods were IT, IAT, IC, IM, and IO in order of applications [107].


## 8. Clinical Use of MSCs

Although MSCs offer remarkable potentials, which made them a favorable candidate for treating a large number of diseases, an overview on statics obtained from the U. S. National Library of Medicine shows that 6205 out of 377,550 research studies are related to clinical stem cell therapy (1.6%) and only 1240 of which are related to MSC-based therapy (0.3%) (Figure2). Still, there are several concerns regarding the cell dosage and the proper administration route and timing [108–110] that limit the use of MSCs in clinical practice.Figure 2
An overview on statics relating to MSC-based therapy clinical trials obtained from the U.S. National Library of Medicine.Some completed clinical trials in this field (all phases except early phase 1 and not applicable) over 2016-2020 have been listed in Table1. Tables 2 and 3 show active recruiting clinical trials on MSC therapy during 2016-2020 (U. S. National Library of Medicine). According to this table, the potential of MSCs has been studied in treating numerous diseases including myocardial infarction, diabetes, spinal cord injury, and systemic lupus. Taking an overall view on these three tables, it has been found completed or active clinical tr ials were mostly related to the nervous system diseases while recruiting clinical trials were mostly related to respiratory diseases. In general, respiratory diseases have been mostly attracted researchers worldwide because of the pandemic COVID-19. In addition, the United States is ranked the first in terms of clinical trials on MSC therapy (Figure 3). Five of these studies (NCT01909154, NCT03473301, NCT02013674, NCT02958267, and NCT02509156) whose results were available have been reviewed in terms of morality rate, adverse effects, and successfulness.Figure 3
Frequency of country contributions in clinical trials on mesenchymal stromal/stem cell-based therapy during 2016-2020 (U. S. National Library of Medicine).NCT01909154 conducted on 12 participants to examine the safety and the impact of the local administration of autologous BM-MSCs in damaged nervous tissue. No mortality was reported in this trial. Adverse effect of urinary tract infection (12/12 or 100%), general pain and back pain (4/12 or 33.33%), myalgia and hyperthermia (3/12 or 25.00%), nasopharyngitis, nausea, muscle contracture, and headache (2/12 or 16.67%), and iron deficiency anemia, diarrhea, saline extravasation, local edema, perineal abscess, infectious mononucleosis, subcutaneous seroma, high level of cholesterol in blood, high level of alkaline phosphatase in blood, thoracic pain, intercostal neuralgia, anxiety, urinary discomfort, pressure ulcer, hemorrhoidectomy, hypertension, hypotension, and orthostatic hypotension (1/12 or 8.33%) were reported. Applying this therapy on 52 patients with spinal cord injury (SCI) showed that administration of BMSCs is safe and may increase the life quality of patients suffering from SCI [111].NCT03473301 (A Study of UCB and MSCs in Children With CP) was conducted on a total number of 91 participants in three groups of allogeneic umbilical cord blood (AlloCB, n=31), cord tissue MSCs (MSC, n=29), and natural history (n=31). The mortality rate was reported zero in this trial. Adverse effect including gastritis, bronchitis viral, respiratory syncytial virus, rhinovirus infection, dehydration, hypoacusis, constipation, diarrhoea, vomiting, fatigue, anaphylactic reaction, influenza, pneumonia, upper respiratory tract infection, infusion related reaction, arthropod bite, tooth avulsion, dehydration, facial paresis, partial seizures, strabismus correction, dental operation, orchidopexy, suture insertion, and tongue tie operation (1/31 or 3.23%), seizure, pyrexia, otitis media, hand-foot-and-mouth disease, and fall, laboratory test abnormal and pyrexia (2/31 or 6.45%), and surgery (3/31 or 9.68%) were observed in the AlloCB group. Upper respiratory tract infection (8/29 or 27.59%), infusion-related reaction, and rash, (4/29 or 13.79%), pyrexia (3/29 or 10.34%), otitis media, rash maculopapular, urticaria, and hospitalisation (2/29 or 6.90%), and tonsillitis, drug hypersensitivity, varicella, fall, disturbance in attention, insomnia, henoch-Schonlein purpura, orchidopexy, adenoidectomy, sleep disorder, anaemia, influenza-like illness, infusion site rash, injection site reaction, and drug hypersensitivity (1/29 or 3.45%) were reported in the MSC group. Seizure (5/31 or 16.13%), strabismus correction, hospitalization, and pyrexia (2/31 or 6.45%), and respiratory tract infection viral, otitis media, fall, fracture, adenotonsillectomy, surgery, thrombocytopenia, bradycardia, gastroesophageal reflux disease, bronchitis, and enterocolitis infectious (1/31 or 3.23%) were observed in the natural history group. Hospitalization (2/27 or 7.41%) and bronchitis, enterocolitis infectious, cough, rash, seizure, respiratory failure, cyclic vomiting syndrome, toothache, and pyrexia (1/27 or 3.70%) were observed in AlloCB after natural history. No article has been published using the results of this trial to discuss about the success of this therapy.The clinical trialNCT02013674 was a phase II study for gaining additional safety and efficacy assessments among two-dose levels previously studied in a phase I setting. Participants included 30 patients suffering from chronic ischemic left ventricular dysfunction secondary to MI scheduled to undergo cardiac catheterization. Two groups of 20 million allogeneic hMSCs (group1, n=15) and 100 million allogeneic hMSCs (group 2, n=15) were designed for this trial. The mortality rate was reported 0.00% (0 l15) and 13.33% (1/15) for group 1 and group 2, respectively. Cardiac failure congestive, cardiac failure (6/15 or 60.00%), hematoma, hypotension (2/15 or 13.33%), and sinus arrest, vertigo, vision blurred, fatigue, gait disturbance, pyrexia, hordeolum, rhinitis, chronic sinusitis, fall, dehydration, spinal column ste, headache, pollakiuria, and asthma (1/15 or 6.67%) were reported in group 1. Cardiac failure congestive, hematuria (3/15 or 20.00%), arteriosclerosis, squamous cell carcinoma, dyspnoea (2/15 or 13.33%), eye pruritus, eye swelling, dysphagia, nausea, chest pain, urinary tract infection, prostatic specific antigen, gout, inguinal mass, pain in extremity, prostatitis, breast mass, cough, epistaxis, alopecia, stasis dermatitis, cardioversion, implantable defibrillator replacement, and tooth extraction (1/15 or 13.33%) were observed in group 2. The results of this study showed the effectiveness of both dosages of cells on reduction of scar size. However, only the 100 million dosages enhanced ejection fraction [112]. Investigation of MSC-therapy for treating osteoarthritis of the knee (NCT02958267) was performed on 32 participants in two groups of BMAC injection and PRP injection (n=17) and Gel-One® hyaluronate injection (n=15). This clinical trial report a mortality rate of zero for all groups and adverse effects of nausea and vomiting (1/17 or 5.88%) for the BMAC injection and PRP injection groups. No data is available about the success of this therapy.The purpose of the clinical trialNCT02509156 was to examine the safety, feasibility, and therapeutic efficacy of allogeneic human-MSCs delivered through transendocardial injection to cancer survivors with left ventricular (LV) dysfunction secondary to anthracycline-induced cardiomyopathy (AIC). 37 subjects in two groups of Allo-MSCs (n=20) and placebo (n=17) were examined in terms of the adverse effect of this trial. A mortality rate of 5.00% and 0% was reported for Allo-MSCs and placebo groups. Serious adverse events including cardiac disorders, sudden cardiac death, procedural pneumothorax, hyperglycaemia, osteoarthritis, transient ischaemic attack, acute kidney injury, and hypotension were reported for the Allo-MSCs group with a total rate of 25.00%. Serious adverse events of cardiac, gastrointestinal, and hepatobiliary disorders, infections and infestations, fall, hyponatraemia, syncope, product issues (lead dislodgement and device lead damage), acute kidney injury, menorrhagia, and hypotension were reported for the placebo group with a total rate of 64.71%. The article published according to the results of this trial does not mention that this therapy is safe or not. The author of this trial stated that if the therapy will be safe and feasible, we will conduct a larger phase II/III trial to examine its therapeutic efficacy [113].


## 9. Future Prospective

The large number of trials focusing on MSCs therapy shows the importance of this therapy from point of view of scientists, and if these trials will be successful, they will change human life positively. Despite the increasing rate of development in MSCs therapy, it has not been commonly used by clinicians because of challenges such as the timing and optimum dosage of MSC administration. There are some conditions that have been treated in preclinical experiments with MSCs but are yet to be translated into clinical trials. Some of these disorders are epilepticus, glioblastoma, hypoxic-ischemic encephalopathy, loss of retinal ganglion cells, nerve regeneration, azoospermia, and nephron generation in kidney cortices (Table4). Therefore, it is encouraged to study the possibility of clinical trials of MSC therapy for such disease in the future. The potential of MSCs brings to mind the idea that the medicine of tomorrow can treat some of the incurable diseases including those related to aging.



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