Challenges And Advances In Clinical Applications Of .

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(2021) 14:24Zhou et al. J Hematol n AccessREVIEWChallenges and advances in clinicalapplications of mesenchymal stromal cellsTian Zhou1,2, Zenan Yuan3, Jianyu Weng1, Duanqing Pei4, Xin Du1*, Chang He2* and Peilong Lai1*AbstractMesenchymal stromal cells (MSCs), also known as mesenchymal stem cells, have been intensely investigated forclinical applications within the last decades. However, the majority of registered clinical trials applying MSC therapyfor diverse human diseases have fallen short of expectations, despite the encouraging pre-clinical outcomes in variedanimal disease models. This can be attributable to inconsistent criteria for MSCs identity across studies and their inherited heterogeneity. Nowadays, with the emergence of advanced biological techniques and substantial improvementsin bio-engineered materials, strategies have been developed to overcome clinical challenges in MSC application. Herein this review, we will discuss the major challenges of MSC therapies in clinical application, the factors impacting thediversity of MSCs, the potential approaches that modify MSC products with the highest therapeutic potential, andfinally the usage of MSCs for COVID-19 pandemic disease.Keywords: Mesenchymal stromal cells, Clinical applications, Heterogeneity, Artificial intelligence (AI), Extracellularvesicles, COVID-19BackgroundMesenchymal stromal cells (MSCs) are pluripotent nonhematopoietic stem cells with self-renewal capability [1]and being intensively investigated in clinical trials. Sincethe discovery of MSCs from bone marrow by Friedenstein in 1970s, MSCs have been isolated from varioussources including muscle, umbilical cord, liver, placenta,skin, amniotic fluid, synovial membrane, and tooth root[2, 3], and tested in amounts of preclinical and clinicalstudies (Fig. 1). It is now understood that MSCs havewide-ranging physiological effects including the maintenance of tissue homeostasis and regeneration [4, 5],as well as the immunomodulatory activities suitable fortherapeutic application [6]. So their indications have been*Correspondence: [email protected]; [email protected];lai [email protected] of Hematology, Guangdong Provincial People’s Hospital,Guangdong Academy of Medical Sciences, Guangzhou 510080, People’sRepublic of China2State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center,Sun Yat-Sen University, Guangzhou 510060, People’s Republic of ChinaFull list of author information is available at the end of the articleexpanded to graft-versus-host disease (GVHD), multiplesclerosis (MS), Crohn’s disease (CD), amyotrophic lateralsclerosis (ALS), myocardial infarction (MI), and acuterespiratory distress syndrome (ARDS) [7–9].Over 300 clinical trials of MSC therapies have beencompleted in patients including but not limited to degenerative or autoimmune diseases (Table 1 lists some of therepresentative completed studies). Overall, MSCs haveexhibited tolerable safety profile and demonstrated promising therapeutic benefits in some clinical settings, whichled to regulatory approvals of MSCs in a few countries.In 2011, the Ministry of Food and Drug Safety (KoreaFDA) approved Cartistem , a MSC product derivedfrom umbilical cord blood and developed by Medipostfor the treatment of traumatic or degenerative osteoarthritis [10]. Thereafter, more MSC products includingHeartiCellgram , Mesoblast, TiGenix, and Stempeutics,were approved by regulatory authorities worldwide forthe treatment of a variety of diseases. In the USA, Ryoncil (remestemcel-L) is promising to be the first FDAapproved GVHD treatment for children younger than 12,but is still in the stage of safety verification. The amount The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, whichpermits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to theoriginal author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images orother third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit lineto the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutoryregulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of thislicence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Zhou et al. J Hematol Oncol(2021) 14:24Fig.1 Various sources of MSCs used in the registered clinical trials.MSCs isolated from bone marrow are most widely applied in clinicaltrials, followed by those from umbilical cord and adipose. MSCs frommuscles, tooth are also usedof clinics offering exogenous stem cell therapies has doubled from 2009 to 2014 in the USA. This boom in stemcell clinics with 351 companies putting stem cells for salein 570 clinics in 2016 indicated the mal-practice of theMSC therapies [11]. Considering the fact that many ofthe applied exogenous stem cell therapies lack confirmation on safety and effectiveness from large-scale clinicaltrials and are even illegal, these medical mal-practices dothreaten the development of MSC therapies [12].In this review, we will focus on the major challenges ofMSC therapies and the underlying factors leading to thefailure of clinical trials. Recent advances and prospectsconcerning the translation of MSC techniques into clinical practices will also be discussed.Challenges in technology transfer of MSCsfrom bench to bedsideAlthough transferring MSCs from bench to bedside istheoretically achievable, substantial failures have beenreported in many early- or late-stage clinical trials, whichaccount for the disapproval of many products by FDA[13]. Factors contributing to the failure of MSC clinicaldevelopment include but not limited to the poor-qualitycontrol and inconsistent characteristics of MSCs in termsof immunocompatibility, stability, heterogeneity, differentiation, and migratory capacity [14, 15] (Fig. 2).Immunocompatibility of MSCsMSCs were immune privileged due to the low expression of MHC-I and HLA-I, and no expression of HLAII or costimulatory factors such as CD40, CD80 andCD86. MSCs can be transplanted as allogeneic cells witha low risk of rejection. Generally, the original MSCs arebelieved to have low immunogenicity [16]. Most MSCproducts are manufactured by amplifying a small number of cells obtained from donors, which can increaseMSC immunogenicity caused by inappropriate processesand culture conditions. After MSCs infusion, the in vivoPage 2 of 24inflammatory molecules in turn increase MSC immunogenicity and further decrease MSCs viability and differentiation capacity, particularly when administratingxenogenic MSCs including human MSCs in animal models [17]. Although the primary immunogenicity of MSCsderived from in vitro experiments might be minimal, thesecondary immunogenicity induced by in vivo positivefeedback loops can cause the absence of efficacy reportedin most clinical trials.Studies have shown that inflammatory molecules(such as interferon-γ), increased cell density, and/orserum deprivation can induce high expression of MHCII in MSCs, while TGF-β suppresses MHC-II expression[18]. The immune compatibility between donors andrecipients is the key to reduce the risk of rejection in theevent of long-term treatments with repeated infusions,in conditions requiring promotion of transplanted bonemarrow integration, or post-renal transplantation rejection treatments [19]. It has been reported that repeatedintra-articular injection of allogeneic MSCs is more likelyto cause an adverse reaction than autologous cells whenadministered in the same manner [20]. The same observations were reported in horses treated with intracellularxenogen-contaminated autologous MSCs (such as FBS)or non-xenogen-contaminated allogeneic MSCs [21].MSCs of high quality is the first step to ensure thesafety and efficacy in clinical trials. Understanding themolecular and cellular mechanisms underlying theimmune incompatibility of MSCs will help to improvethe manufacture of MSC products.Stemness stability and differentiation of MSCsMSCs have mesodermal lineage differentiation potentialand the potential to regulate tissue regeneration by mediating tissue and organ repair, as well as replacing damaged cells [22]. Different tissue-derived MSCs exhibittendencies to differentiate into different end-stage lineage cells [23, 24], and such regeneration and differentiation contribute to distinctive clinical efficacy.Several laboratories have analyzed the proteomemodifications associated with MSCs differentiation [25,26]. They indicated that ‘‘stemness’’ genes were highlyexpressed in undifferentiated and de-differentiated MSCs[27, 28]. These highly stemness-related gene clustersin MSCs have been found to be mainly involved in theproliferation, differentiation, and migration [29]. WhenMSCs differentiated into osteoblasts, chondrocytes,and adipocytes, expressions of these genes significantlydecreased, underlining their unique characteristics.Table 2 lists typical stemness genes of MSCs.Serial passaging in long-term culture could negativelyaffect the expression of stemness genes [48, 49]. A previous study indicated that CD13, CD29, CD44, CD73,

Zhou et al. J Hematol Oncol(2021) 14:24Page 3 of 24Table 1 Some representative registered clinical trials of MSC therapiesNCT man Mesenchymal Stromal Cells For Acute Respiratory DistressSyndrome (START)Phase 2National Heart, Lung, and Blood Institute (NHLBI)Massachusetts General HospitalStanford UniversityUniversity of PittsburghUniversity of MinnesotaOhio State UniversityUniversity of California, San FranciscoNCT00957931Allo-HCT MUD for Non-malignant Red Blood Cell (RBC) Disorders:Sickle Cell, Thal, and DBA: Reduced Intensity Conditioning, Co-txMSCsPhase 2Stanford UniversityUniversity of MinnesotaUniversity of Alabama at BirminghamNCT01771913Immunophenotyping of Fresh Stromal Vascular Fraction FromAdipose-Derived Stem Cells (ADSC) Enriched Fat GraftsPhase 2University of Sao PauloNCT01909154Safety Study of Local Administration of Autologous Bone MarrowStromal Cells in Chronic Paraplegia (CME-LEM1)Phase 1Puerta de Hierro University HospitalNCT03102879Encapsulated Mesenchymal Stem Cells for Dental Pulp RegenerationPhase 1Phase 2Universidad de los Andes, ChileCells for Cells, ChileNCT02467387A Study to Assess the Effect of Intravenous Dose of (aMBMC) toSubjects With Non-ischemic Heart FailureN/ACardioCell LLCStemedica Cell Technologies, IncNCT02387749Effect Of Mesenchymal Stem Cells Transfusion on the Diabetic Peripheral Neuropathy PatientsN/ACairo UniversityNCT01932164Use of Mesenchymal Stem Cells for Alveolar Bone Tissue Engineeringfor Cleft Lip and Palate PatientsN/AHospital Sirio-LibanesNCT02481440Repeated Subarachnoid Administrations of hUC-MSCs in Treating SCIPhase 1Phase 2Third Affiliated Hospital, Sun Yat-Sen University, ChinaNCT02165904Subarachnoid Administrations of Adults Autologous MesenchymalStromal Cells in SCIPhase 1Emory UniversityNCT02330978Intravitreal Mesenchymal Stem Cell Transplantation in AdvancedGlaucomaPhase 1University of Sao PauloNCT01183728NCT01586312Treatment of Knee Osteoarthritis With Autologous/ Allogenic Mesenchymal Stem CellsPhase 1Phase 2Red de Terapia CelularFundacion Teknon, Centro Medico Teknon, BarcelonaUniversity of ValladolidNCT02037204IMPACT: Safety and Feasibility of a Single-stage Procedure for FocalCartilage Lesions of the KneePhase 1Phase 2UMC UtrechtNCT02958267Investigation of Mesenchymal Stem Cell Therapy for the Treatment ofOsteoarthritis of the KneePhase 2OhioHealthNCT00587990Prospective Randomized Study of Mesenchymal Stem Cell Therapy inPatients Undergoing Cardiac Surgery (PROMETHEUS)Phase 1Phase 2National Heart, Lung, and Blood Institute (NHLBI)Johns Hopkins University Specialized Center for Cell Based TherapyThe Emmes Company, LLCUniversity of MiamiNCT01385644A Study to Evaluate the Potential Role of Mesenchymal Stem Cells inthe Treatment of Idiopathic Pulmonary FibrosisPhase 1The Prince Charles HospitalMater Medical Research InstituteNCT02509156Stem Cell Injection in Cancer SurvivorsPhase 1The University of Texas Health Science Center, HoustonNational Heart, Lung, and Blood Institute (NHLBI)NCT02379442Early Treatment of Acute Graft Versus Host Disease With Bone Marrow- Phase 1Derived Mesenchymal Stem Cells and CorticosteroidsPhase 2National Heart, Lung, and Blood Institute (NHLBI)National Institutes of Health Clinical Center (CC)NCT01087996The Percutaneous Stem Cell Injection Delivery Effects on Neomyogen- Phase 1esis Pilot Study (The POSEIDON-Pilot Study)Phase 2University of MiamiNational Heart, Lung, and Blood Institute (NHLBI)The Emmes Company, LLCNCT02013674The TRansendocardial Stem Cell Injection Delivery Effects on Neomyo- Phase 2genesis Study (The TRIDENT Study)The Emmes Company, LLCUniversity of MiamiNCT01392625PercutaneOus StEm Cell Injection Delivery Effects On Neomyogenesisin Dilated CardioMyopathy (The POSEIDON-DCM Study)Phase 1Phase 2National Heart, Lung, and Blood Institute (NHLBI)University of MiamiNCT00768066The Transendocardial Autologous Cells (hMSC or hBMC) in IschemicHeart Failure Trial (TAC-HFT)Phase 1Phase 2University of MiamiThe Emmes Company, LLCNCT00629018Safety and Efficacy Study of Stem Cell Transplantation to Treat DilatedCardiomyopathyPhase 2University Medical Centre LjubljanaBlood Transfusion Centre of SloveniaStanford UniversityNCT00927784Effect of Intramyocardial Injection of Mesenchymal Precursor Cells onHeart