Allogeneic Vs. Autologous Mesenchymal Stem/stromal Cells In Their .
Cell & Bioscience(2021) 11:187Li et al. Cell en AccessREVIEWAllogeneic vs. autologous mesenchymalstem/stromal cells in their medication practiceChenghai Li1*† , Hua Zhao2†, Linna Cheng3† and Bin Wang4*AbstractMesenchymal stem/stromal cell (MSC)-based therapeutics is already available for treatment of a range of diseasesor medical conditions. Autologous or allogeneic MSCs obtained from self or donors have their own advantages anddisadvantages in their medical practice. Therapeutic benefits of using autologous vs. allogeneic MSCs are inconclusive. Transplanted MSCs within the body interact with their physical microenvironment or niche, physiologically orpathologically, and such cells in a newly established tissue microenvironment may be impacted by the pathologicalharmful environmental factors to alter their unique biological behaviors. Meanwhile, a temporary microenvironment/niche may be also altered by the resident or niche-surrounding MSCs. Therefore, the functional plasticity and heterogeneity of MSCs caused by different donors and subpopulations of MSCs may result in potential uncertainty in theirsafe and efficacious medical practice. Acknowledging a connection between MSCs’ biology and their existing microenvironment, donor-controlled clinical practice for the long-term therapeutic benefit is suggested to further considerminimizing MSCs potential harm for MSC-based individual therapies. In this review, we summarize the advantagesand disadvantages of autologous vs. allogeneic MSCs in their therapeutic applications. Among other issues, wehighlight the importance of better understanding of the various microenvironments that may affect the properties ofniche-surrounding MSCs and discuss the clinical applications of MSCs within different contexts for treatment of different diseases including cardiomyopathy, lupus and lupus nephritis, diabetes and diabetic complications, bone andcartilage repair, cancer and tissue fibrosis.Keywords: Mesenchymal stem/stromal cell, Single-nucleotide polymorphism, Stem cell heterogeneity, Stem cellmicroenvironment, Stem cell transplantationIntroductionMSCs, referred to as mesenchymal stem/stromal cells,can differentiate towards mesoderm-derived cell lineages such as osteocytes, adipocytes, and chondrocytes[1, 2]. The existence of MSCs in bone marrow (BM) wasfirst suggested by the German pathologist Cohnheim150 years ago [3]. MSCs were initially described and*Correspondence: chenghai li@yahoo.com; bin.wang201166@hotmail.com†Chenghai Li, Hua Zhao and Linna Cheng contributed equally to thiswork1Stem Cell Program of Clinical Research Center, People’s Hospitalof Zhengzhou University, 7 Weiwu Road, Zhengzhou 450003, China4Department of Neurosurgery, People’s Hospital of ZhengzhouUniversity, 7 Weiwu Road, Zhengzhou 450003, ChinaFull list of author information is available at the end of the articleidentified in the 1970s as the discrete “fibroblast” colonies of the BM by Friedenstein et al. [4, 5]. Such cellsare currently well known to be localized in the multiple types of adult tissues, including BM, adipose tissue(AT), peripheral blood [2], and human embryo tissues,such as fetal liver [6], fetal BM [7], aorta-gonad-mesonephros and yolk sac [8], as well as various neonatal birthassociated tissues, including placenta, umbilical cord(UC), Wharton’s jelly (WJ) and cord blood [2, 9]. MSCscan originate from perivascular or mural cells as well,i.e., pericytes, from nearly all vascularized tissues [10,11]. Due to the diverse tissue-specific properties, MSCsderived from different tissues exhibit the varied phenotypic properties and functional behaviors [12, 13]. In the 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://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
Li et al. Cell Biosci(2021) 11:187late 1980s, Caplan coined the name “mesenchymal stemcell” based on several key facts such as [14]: (i) embryonicmesenchymal cells in the chick and mouse/human limes;(ii) multi-lineage of mesenchymal cells; (iii) self-renewaland multipotent differentiation in vitro; and (iv) bioactivefactors in bone for self-cell repair skeletal defects. Sincethen, the stem cell properties of “mesenchymal stem cell”remain actively controversial. Given that the multipotency of MSCs in vivo is not known, Caplan proposed torename the MSCs as Medicinal Signaling Cells in 2010to more accurately reflect their immunomodulatory andtrophic functions [15]. In 2019, the Mesenchymal andTissue Stem Cell Committee of the International Society for Cellular Therapy (ISCT) suggested a change innomenclature from “mesenchymal stem cell” to “mesenchymal stromal cell”, which is to further consolidate andclarify ISCT’s MSC committee position on functionaldefinition of mesenchymal stem versus stromal cells [16].Given their self-renewal and differentiation properties, immunomodulatory capabilities, lacking majorhistocompatibility complex (MHC) class II molecules,migration and tissue remodeling potential, MSCs haveattracted much attention for stem cell-based translationalmedicine research. The first phase I clinical trial usingautologous BM-derived MSCs was conducted by Lazaruset al. in 1995 in 15 patients with complete clinical remission of hematological malignancies [17]. Since then,studies exploring the capability of MSCs in translationalmedicine are being grown in a remarkable way. Unfortunately, clinical trial failures have frequently appeared forMSC-based therapies [18–20] and, however, rigorouslyclinical evidence of the therapeutic benefits of MSCs isstill lacking. The precise mechanisms of MSCs’ action arenot fully understood and there is still a lot to learn.Clinical applications of autologous vs. allogeneicMSCsAdvantages and disadvantages in autologousand allogeneic MSCsClinical applications of autologous and allogeneic MSCsare already available for treating a range of diseases orconditions. Autologous MSCs are easy to obtain andlacking of immune rejection after infusion. Nevertheless, autologous MSCs require a few weeks for isolation, in-vitro expansion and release and patient-derivedautologous MSCs may underlie systemic diseases. Allogeneic MSCs can offer several advantages such as donorselection, various sources, low immunogenicity, andoff-the-shelf availability. Allogeneic MSCs may be alsoimmunogenic and such cells can induce an immunememory response under appropriate condition [21–23],Page 2 of 21albeit MSCs have been believed to be immune-privilegedor immunocompromised. Joswig et al. conducted anin vivo study to assess the clinical response to repeatedintra-articular injection of autologous and allogeneicMSCs and found a significant adverse response of thejoint to allogeneic MSCs after a second injection, suggesting an adaptive immune response to the injectedallogeneic MSCs but not autologous MSCs [24]. In contrast, Huang et al. [25] observed that the implanted allogeneic MSCs expressed the high levels of MHC-Ia andMHC-II by 14 days in an myocardial infarction (MI) ratmodel after cell implantation and therapeutic benefitswere lost within 5 months, which also suggests a transition from an immunoprivileged to an immunogenicstate after differentiation of MSCs. Currently, allogeneicMSC therapy is increasing in clinical translational fieldand these cells have been shown to be clinically safe andeffective. To minimize any potential anti-donor immuneresponses, several strategies are suggested by Lohanet al. in their systematic review [26], including the use ofimmunosuppressive drugs. However, the potential risksand limitations of using autologous vs. allogeneic MSCsfor therapeutic applications are still highly debated suchas the potential impact of donor–donor heterogeneity. Ingeneral, allogeneic and autologous MSCs have their ownadvantages and disadvantages in the preclinical and clinical practice (Fig. 1).Short‑term lifespan and benefit of infused MSCsOwe to MHC-unrestricted property of MSCs, a numberof clinical trials using allogeneic MSCs or MSC-basedtherapeutic products are being carried out for treatmentof a variety of medical conditions. Given the low engraftment efficiency of MSCs, only a limited number of suchcells can migrate and reach the disease target sites aftersystemic transplantation [27–29]; thus limit their clinicalefficacy. Pulmonary passage seems to be a major obstacle for intravenous MSCs delivery for regenerative tissue therapy in preclinical studies [30, 31]. Those in vivostudies suggest that MSCs exert their therapeutic influence through the secretion of soluble protein/peptidemolecules. MSCs have a short-term lifespan after systemic infusion and the most circulating MSCs, allogeneic or even autologous, will be lysed by the humoralcomponents and immune cell subsets [32]. While a largenumber of in vivo studies have shown the short lifespanof MSCs through tracking intravenously administeredMSCs, clinical data are rare for tracking MSC hominginto different tissues within the transplanted patients.von Bahr et al. previously examined autopsy materialfrom 18 patients who were infused with MSCs and 108
Li et al. Cell Biosci(2021) 11:187Page 3 of 21Fig. 1 Allogeneic vs. autologous MSCs: advantages and disadvantages. MSCs obtained from donors and self have their own advantages anddisadvantagestissue samples from 15 patients were analyzed for MSCdonor DNA to evaluate engraftment of MSCs [33]. MSCdonor DNA was detected in 9/13 MSC infusions within50 days from MSC infusion to sample collection and in2/8 earlier MSC infusions within 75 and 87 days, respectively. A negative correlation was observed between thedetection of MSC donor DNA and the time from MSCinfusion to sample collection [33]. Consequently, thefindings in this study indicate that systemically administered MSCs have a relatively short life in the recipients,suggesting that MSCs may exert their short-term therapeutic benefits.In specific contexts, therapy with MSCs can improveshort-term recovery for diseases or conditions such asacute respiratory distress syndrome (ARDS). ARDS isassociated with acute inflammatory lung injury, lungpermeability and edema [34] and hospital mortality inpatients with ARDS remains high with 34.9% for thosewith mild, 40.3% with moderate, and 46.1% with severeARDS [35]. Hospitalized severe patients with coronavirus disease 2019 (COVID-19) pneumonia require to betreated in the intensive care unit (ICU) due to pneumonia complications, including 61.1% of these patients withARDS [36]. There is a growing interest in using of MSCsor MSC-derived therapeutic products as a potential newtreatment for ARDS. However, the precise mechanismsof action of MSCs remain to be fully investigated. Arecent systematic review highlights several potentialtherapeutic mechanisms of MSCs in ARDS [37], including immunomodulatory effects on immune and inflammatory cells, maintaining the alveolar epithelial andendothelial barrier through paracrine factors secreted byMSCs, reducing endoplasmic reticulum stress, and antifibrotic potential of MSCs in ARDS. Two recent phase1/2a randomized controlled clinical trials report thetherapeutic benefits of using UC-derived MSCs in subjects with COVID-19 ARDS mainly through anti-inflammatory and immunomodulatory activities [38, 39], whichindicates a set of inflammatory cytokines downregulatedat the day 6 after infusion. The therapeutic potential ofMSCs has been observed in a case series study, whichsuggests the improved PaO2/FiO2 ratio, the ratio of arterial oxygen partial pressure to fractional inspired oxygen,in severe COVID-19-induced ARDS patients in ICU withcritically hypoxemia [40]. Due to the physical propertiesof MSCs, the issue of exogenous MSC engraftment afterinfusion remains actively controversial. To avoid cellrelated problems, MSC-derived exosomes have attractedgreat interest in recent years in translational biomedicinefield. One open-label cohort study conducted by Sengupta et al. [41] demonstrates the clinical presentation
Li et al. Cell Biosci(2021) 11:187and oxygenation improved in severe COVID-19 patientswith moderate-to-severe ARDS after treatment withexosomes secreted by BM-derived MSCs. To extend ourdiscussion, MSCs cultured under hypoxic condition havea high expression of chemokine stromal-derived factor-1receptors, CXCR4 and CXCR7, to promote MSCs’ migration [42]. When MSCs are cultured under long-term(10 days) hypoxia, such cells downregulate their surfacemarkers including CD44 and CD105 [43]. Theoretically,exogenous MSCs may exert their short-term effects toimprove ARDS or other infectious diseases through theimmediate anti-inflammation and immunomodulation and this is also specific therapeutic characteristic ofMSCs. However, therapy with MSCs for ARDS still confronts many challenges including safety issues, low survival ability, engraftment and migration after infusionas well as the optimized cell preparation, dose, infusionroute, study subjects, and the window period.Therapeutic effects of autologous vs. allogeneic MSCsAutologous and allogeneic MSCs have their own advantages and disadvantages and, on an individual therapeutic basis, clinical applications of autologous or allogeneicMSCs need to be designed to maximize their therapeuticactivity while to minimize their potential side effects. Inthis section, we summarize the clinical applications usingautologous vs. allogeneic MSCs in various fields of translational biomedicine (Table 1). We then extend our discussion and analyze a bidirectional interaction betweenthe transplanted autologous or allogeneic MSCs and theirexisting harmful or non-harmful niche environments (aswill be discussed later). Finally, we conclude with a summary of therapeutic limitation of using autologous orallogeneic MSCs for long-term beneficial therapies forthe stem cell transplant recipients.CardiomyopathyClinical trials have shown that the therapeutic benefits ofusing autologous vs. allogeneic MSCs are inconclusive,while therapy with such cells appears to be undoubtedlysafe. One early clinical study reported that intramyocardial or intracoronary autologous BM-derived MSC treatment was safe and effective for chronic severe dilatedcardiomyopathy (DCM) [44], as showed the improvement of left ventricular function and scar reduction inthese patients. However, this trial for autologous MSCswas limited by the small sample size and also lacked acontrol arm. Gao et al. [45] previously designed a randomized and multicenter trial to assess 2-year follow-upsafety and efficacy of autologous BM-derived MSCs forPage 4 of 21treatment of acute MI. This study by Gao et al. showedthat, compared with baseline, improvement of myocardial ischemia in patients treated with intracoronary infusion of autologous BM-derived MSC as well as in thecontrol group with standard medical treatment. Of note,no significant difference was observed between the bothgroups about myocardial viability and function in theclinical setting [45]. Preliminary positive results in otherstudies suggested that autologous BM-derived MSCs aresafely and effectively administered to treat patients suffering from ischemic heart diseases [46–48].Therapeutic safety and efficacy of using allogeneic BMderived MSCs was reported in a randomized, doubleblind, placebo-controlled clinical trial for treatment ofacute MI [49], as showed the improvement in left ventricular ejection fraction and remodeling in MSC-treatedpatients. In contrast, one previous POSEIDON randomized trial was designed to test the safety and efficacyof allogeneic vs. autologous MSCs in patients with nonischemic DCM [50]. Based on clinical results in the study[50], allogeneic MSCs were seemly to be superior to theself-derived MSCs, as illustrated significant improvement in ejection fraction, Six Minute Walk Test, Minnesota Living with Heart Failure Questionnaire scores,and endothelial function. In another POSEIDON randomized trial, allogeneic and autologous BM-derivedMSCs were delivered via transendocardial injection in 30patients with ischemic cardiomyopathy [51]. The studydemonstrated that therapy with allogeneic and autologous MSCs improved functional status and quality oflife in these patients [51] and no difference was observedbetween the cell types.As aforementioned, therapy with MSCs, autologousor allogeneic, improves left ventricular ejection fraction, decreases scar size, reverses ventricular remodelingalong with eliciting the cell secretion of paracrine factors, although the exact mechanism of action of MSCsremains to be further investigated. However, therapeutic benefit is modest and there are frequently combinedclinical results for MSC intervention in patients withischemic cardiomyopathy [52, 53]. Of note, the microenvironment in infarction heart may be harmful to transplanted MSC survival due to high concentration of freeradicals [54, 55]. One previous in vivo study showed thatintro-myocardial injection of bone marrow cells (BMCs)from post-MI donor mice led to impaired therapeuticefficacy of BMCs for treatment of MI [56], which indicates impairment of BMCs by severe donor MI. Thestudy further deliberated that MI induced inflammatorystate and pro-inflammatory alteration of bone marrow
BMBMAutoAlloPhase I trialRandomized and controlled trialPhase I/II trialBMBMBMUCLupus/lupus nephritis AutoAlloAlloAlloPhase I/IIPhase I/IICase series studyCase series studyPhase I/IIBMAutoPhase I trialAllo vs. auto BMBMAutoRandomized and controlled trialPhase afety of the intervention of allo or auto MSCsand great improvement in EF, 6MWT, MLHFQ, andendothelial restoration in allo compared to auto MSCinjection in patients with chronic non-ischemic dilatedcardiomyopathyImprovement in left ventricular EF and remodeling inMSC-treated patients with acute myocardial infarctionMixed clinical outcomes presented, as showed 32.5%and 27.5% of patients with MCR and PCR to MSCinfusion, respectively, and 12.5% and 16.7% of patientswith disease relapse at 9 and 12 months of follow-up,respectivelyImprovement of clinical outcomes and decrease ofserological autoimmune markers at 1-year follow-upComplete or partial remission of SLE after MSC infusionthrough a 9-month follow-upNo change in SLE activity indexes but increase in Tregulatory cells during 14 weeks of follow-up[63][62][61][57][51][50][49]Improvement in end-systolic volume, EF, stroke volume, [48]cardiac output and myocardial mass at 6 monthsfollow-up in MSC-treated patients with chronic ischaemic heart failureImprovement in cardiac performance, left ventricularremodeling, and patient quality of lifeCardiac function and quality of life improved in patients [46]with ischemic heart disease undergoing cardiac surgical revascularization at one-year follow-upNo improvement in myocardial viability and function in [45]acute STEMI patientsImprovement of clinical symptoms and left ventricularfunction in patients with chronic severe refractorydilated cardiomyopathyTherapeutic effectSerially escalated: 20, 100, or 200/10 LV sites Improvement in functional status and quality of life inpatients with ischemic cardiomyopathy100/10 LV sitesDose-ranging (0.5, 1.6 and 5/kg)77.5 67.9 (inter-quartile range 53.8)61.5/10–16 viable sitesN/A3.08 0.520.5–1.0/kg or 2.0–3.0/kg( 106 cells)PhaseCohort trialSingle dose of MSCsStudy category/Allo vs. auto tionTable 1 Summary of clinical studies with autologous and allogeneic MSCsLi et al. Cell Biosci(2021) 11:187Page 5 of 21
BMBMWJBMUCAutoAlloAlloAlloAlloAllo vs. auto ATBMAutoSourceBMAuto/alloDM/DM complication AutoDisease/conditionTable 1 (continued)1.1/kg150 or 3001.0/kgDose-escalating, 0.3, 1.0 or 2.0/kg3/kgN/AOpen-labeled and two-armed trial 103.14 mL with 2.65 0.8 104 ISCs/kg or95.33 mL with 2.07 0.67 104 ISCs/kgPhase I/IIPhase I/IIPhase I/IIPhase I/IIPilot trialPhase IN/A( 106 cells)PhaseRandomized and controlled trialSingle dose of MSCsStudy category/[72][71][70]References[75][74]Reduction in insulin requirement and a better longterm hyperglycemia control in type 1 DM patientstreated with co-infusion of auto insulin-secreting MSCsand BM-derived HSCs, compared with allo stem celltherapy[77]Metabolic improvement in type 1 DM patients treated [76]with MSC transplantation in combination with auto BMmononuclear cellsImprovement in glomerular filtration rate at 12 weekspost-infusion in patients with DM nephropathyTherapeutic potential in type 2 DM, as showed theimprovement in laboratory parameters and systemicinflammationSafety and feasibility of MSC therapy for type 2 DM dur- [73]ing a 12-week periodTherapeutic safety and effectiveness in diabetic retinopathySafe and effective therapeutic option for BullosisdiabeticorumImprovement of healing in type 2 DM patients withcritical limb ischemia after 24 weeks of follow-upTherapeutic effectLi et al. Cell Biosci(2021) 11:187Page 6 of 21
BMATATBMBMATPlacenta Pilot trialUCAutoAutoAutoAlloAlloAlloAlloAlloPhase I/IIRandomized and controlled trialPhase I/IIPhase IIPhase IIbPhase IIbPhase I/IIPhase I/IIBM2050–603.9 or 6.740Dose escalation: 20, 50, 75, or 1505010010 or 10010 or 100( 106 cells)PhaseAutoSingle dose of MSCsStudy category/Bone/cartilage repairSourceAuto/alloDisease/conditionTable 1 (continued)Improvement in pain and clinical outcomes in osteoarthritis patientsSafety in intra-articular injection of MSCs and clinicalimprovements at 24-week follow-upImprovement in pain scores and quantitative MRIassessmentsImprovement of both pain and cartilage qualitywithout major adverse events in patients with kneeosteoarthritisTreatment of knee osteoarthritis with a twenty-fivemillion-cell dose of MSCs shown a trend toward painreductionClinical and functional improvement and cartilageregeneration in patient with knee osteoarthritis at12 months of follow-upClinical and functional improvement and pain reliefin patients with knee osteoarthritis at 6 months offollow-upClinical and functional improvement of knee osteoarthritis after intra-articular injection of MSCs versushyaluronic acid during follow-up of 4 yearsClinical and functional improvement of knee osteoarthritis after intra-articular injection of MSCs versushyaluronic acid during follow-up of 12 monthsTherapeutic esLi et al. Cell Biosci(2021) 11:187Page 7 of 21
BMBMUCUCBMBMBMBMBMPlacenta Phase ase I/IIPhase IPhase IIPhase IPhase IIRetrospective studyCohort studyCohort studyPhase IPhase I/IIPhase I1.0/kg1.0 or 2.0/kg20, 100, or 20050100506.81/kgN/A1.14/kg1.0 or 2.0/kg3.0/kg1.0 or 1.5/kg1.0–2.2/kg[95][94]ReferencesImprovement of lung function and computed tomography imaging after MSC infusion combined withplasmapheresis in systemic sclerosis patients[117][116][115]Safety of a single of MSC infusion up to 2 108 cells/infusion in IPF patientsFeasibility and short-term safety of MSC infusion inpatient with IPF[114][113][112][111][110][98][97]Reduction of hepatic fibrosis and improvement of liverfunction in patients with liver cirrhosisImprovement in laboratory parameters such as liverfunction and quality of life for patients with liver cirrhosisHistological improvement in 54.5% patients with alcoholic liver cirrhosis following MSC therapyResponse rate to MSC infusion among 50% patientswith steroid-refractory acute GVHD III/IVEnhancement of hematopoietic recovery when cotransplantation of MSCs and cord blood in high-riskleukemia patientsEnhancement of hematopoietic recovery and reduction of GVHD incidence in acute leukemia childrenwhen co-transfusion of MSCs and HSCsSafe MSC infusion in prostate cancer patients but nohoming of MSCs to the primary tumors at sufficientlevelsSafe and tolerable treatment with MSC infusion in com- [96]bination with ganciclovir in patients with advancedgastrointestinal adenocarcinomaSafety and feasibility of MSC infusion in combinationwith ganciclovir in patients with advanced gastrointestinal adenocarcinomaRapid hematopoietic recovery after co-infusion of autoMSCs and auto peripheral blood progenitor cells inpatients with advanced breast cancerTherapeutic effect(2021) 11:1876MWT Six Minute Walk Test, Allo allogeneic, AT adipose tissue, Auto autologous, BM bone marrow, BMDM diabetes mellitus, EF ejection fraction, HSCs hematopoietic stem cells, IPF idiopathic pulmonary fibrosis, ISCsinsulin-secreting MSCs, kg kilogram body weight, LV left ventricular, MCR major clinical response, MLHFQ Minnesota Living with Heart Failure Questionnaire, MRI magnetic resonance imaging, N/A not available, PCR partialclinical response, SLE systemic lupus erythematosus, STEMI ST-segment elevation myocardial infarction, UC umbilical cord, WJ Wharton’s jellyTissue fibrosisBMAutoPhase I/IIBM( 106 cells)PhaseAutoSingle dose of MSCsStudy le 1 (continued)Li et al. Cell BiosciPage 8 of 21
Li et al. Cell Biosci(2021) 11:187composition [56]. Of clinical relevance, this study suggests that implantation of autologous BMCs, in contrast,is likely to be less efficacious.Lupus and lupus nephritisTransplanted autologous BM-derived MSCs were notshown to be clinically efficacious in response to treatment through the week 14 in two system lupus erythematosus (SLE) patients, albeit no adverse effects were noted[57]. An early in vitro and in vivo study showed that BMderived MSCs from SLE patients had the abnormalitiesof cytokine expression profiles and the population doubling time [58]. BM-derived MSCs from SLE patientsalso demonstrated the early sign of senescence, theincreased telomerase activity [59]. Gene expression profile in another study also revealed the biological abnormalities of BM-derived MSCs from SLE patients, such asactin cytoskeleton, cell cycling regulation, bone morphogenetic protein-5 as well as activated mitogen-activatedprotein kinase and dysregulation in transforming growthfactor-β signaling pathways [60].Therapeutic potential of allogeneic BM-derived MSCsfor lupus nephritis was reported in an SLE case carriesstudy [61]. In this clinical trial [61], three SLE patientswith class IV active proliferative nephritis were treatedwith allogeneic BM-derived MSCs and SLEDAI (SLE disease activity index) scores revealed that disease remissionwere complete for two patients and partial for the thirdone after 9 months of follow-up. Therapy with allogeneicBM-derived MSCs was also reported in a pilot clinicaltrial [62]. This study demonstrated the clinical improvement in 12 of 13 patients with a marked decrease in theSLEDAI score at 12-month follow-up and the decreasedserum titres of anti-dsDNA antibody, one of SLE markerauto-antibodies, from baseline for 1 month and 3 monthspost transplantation, respectively [62]. A multicenterclinical study showed that transplanted allogeneic UCderived MSCs were safe and effective in severe andrefractory SLE and, however, therapeutic effect may benot permanent, reflected that 12.5% and 16.7% of SLEpatients had disease relapses after 9 and 12 months offollow-up, respectively [63].SLE is an autoimmune disease characterized by themultiple of autoantibody production and the multiple oforgan complications. Therapy with MSCs from healthydonor individuals without relation to genetic variantsis increasing in prevalence in SLE. Prior studies haveshown the genetic factors contributing to MSC dysfunction in SLE [64–66]. For instance, HLA-DM and HLA-Gare identified in SLE [67] and HLA-G is associated withPage 9 of 21immunosuppressive property of MSCs [68]. Patientself-derived MSCs are believed to have impaired immunosuppressive capacity in innate and adaptive immuneresponses partly due to the abnormal genetic background[69]. In this regard, autologous MSCs may not be eligiblefor therapeutic option in SLE.Diabetes mellitus (DM) and DM complicationMSCs have also shown therapeutic potential for DMand DM complications. Both autologous and allogeneicMSCs are widely used for treating individuals with type 1and 2 DM (T1DM and T2DM). Therapeutic potential ofautologous BM-derived MSCs revealed in T2DM criticallimb ischemia and foot ulcer [70] and lower limb bullosis diabeticorum [71]. The use of autologous BM-derivedMSCs for the treatment of diabetic retinopathy was alsoevaluated in a pilot clinical trial and this study suggestedautologous MSCs as a potentially safe and effective treatment option for diabetic retinopathy [72]. Laboratoryparameters and clinical trial data in the trial [72] showeda significant decrease in the levels of fasting blood glucose and serum C-reactive protein from baseline at 1-,3-, and 6-month follow-up and a significant improvement in best corrected visual acuity after 3 and 6 months,respectively.Clinical data from T2DM individuals documentedsafety and effectiveness of allogeneic BM-derived MSCs[73] and WJ-derived MSC [74]. Allogeneic BM-derivedMSCs were also shown to be safe and improved diabet
mesenchymal cells in the chick and mouse/human limes; (ii) multi-lineage of mesenchymal cells; (iii) self-renewal and multipotent dierentiation in vitro; and (iv) bioactive factors in bone for self-cell repair skeletal defects. Since then, the stem cell properties of "mesenchymal stem cell" remain actively controversial. Given that the multipo-
The bone marrow-derived mesenchymal stem cell implantation procedure was very well tolerated with no reported adverse events. Conclusions: Our study reveals promising improvement of premature ovarian failure-related clinical manifestations in two patients after intraovarian autologous bone marrow-derived mesenchymal stem cells engraftment.
niche can be colonized by autologous stem cells derived from other tissues. In some areas of medicine, autologous stem cells are already used in clinical practice for the repair of damaged tissues and organs, although these methods are still experimental [21,22]. There were several publications about the use of stem cells for improving the
Stem cell transplantation is a procedure in which a patient receives healthy stem cells to replace damaged stem cells. There are two types of SCT: {{Autologous transplantation uses the patient's own stem cells. These cells are collected from the patient and stored for transplantation. {{Allogeneic transplantation uses stem cells from a donor .
mesenchymal stem cells. Larger mesenchymal stem cell yields are more desirable for research and clinical application. See commentary on page 1844 R ecent advances in stem cell technology have begun to realize the therapeutic regenerative po-tential of mesenchymal stem cells (MSCs).1,2 As new experiments are performed in various fields of medicine,
RESEARCH Open Access Comparative efficacy of tandem autologous versus autologous followed by allogeneic hematopoietic cell transplantation in patients . 4Center for Evidence-Based Medicine and Health Outcomes Research, University of South Florida, Morsani College of Medicine, 12901 Bruce B. Downs Boulevard, MDC 27, Tampa, FL 33612, USA
use ASC pellet for clinical application. Key Words: Adult stem cell, Mesenchymal stem cell, Regenera-tive medicine, Cell- and tissue-based therapy. Introduction Adipose-derived stem cells (ASCs) are mul-tipotent mesenchymal stem cells (MSCs) whose differentiation potential is similar to that of other MSCs1. They exhibit definitive stem cell char-
Particularly, we summarize the recent clinical trials performed to evaluate the safety and efficacy of MSC exosomes. Overall, this paper provides a general overview of MSC-exosomes as a new cell-free therapeutic paradigm. Keywords: Exosomes, Mesenchymal stem cell, Clinical trial, Disease Background Mesenchymal stem/stromal cells (MSCs) are one .
Basic Description Logics Franz Baader Werner Nutt Abstract This chapter provides an introduction to Description Logics as a formal language for representing knowledge and reasoning about it. It first gives a short overview of the ideas underlying Description Logics. Then it introduces syntax and semantics, covering the basic constructors that are used in systems or have been introduced in the .
