Mesenchymal stem cells

About 40 years ago Friedenstein described stromal cells in the bone marrow that were spindle shaped and proliferate to form colonies. These cells attach to plastic and are able to differentiate under defined in vitro conditions into multiple cell types present in many different tissues, e.g. osteoblasts, chondroblasts, adipocytes, etc. Later on these cells, obtained from postnatal bone marrow, were called mesenchymal stem cells (MSC) or stromal stem cells. Recently the presence of somewhat similar cells has been demonstrated in many other tissues too. In spite of extensive attempts to characterize these cells we are still lacking definitive in vivo markers of MSC although retrospective functional data strongly support the existence of common adult stem cells that have the capacity to differentiate along various specific differentiation lineages. Since MSC can be rather easily isolated from the bone marrow and can also be expanded in vitro they have become a prime target for researchers of tissue regeneration. These cells have now been extensively used for transplantation experiments in animals and also for some therapeutic trials in humans. However, much new research is needed to learn enough on the molecular mechanisms of MSC differentiation to evaluate their full capacity for tissue regeneration.     

间质干细胞与免疫调节

目的:间质干细胞能够逃避免疫识别,抑制免疫反应特征。文章就近年来间质干细胞及其免疫调节作用进行综述。资料来源:应用计算机检索PUBMED 1976-01/2006-01期间的相关文章,检索词为"mesenchymal stem cells,immune modulation",并限定文章语言种类为English。资料选择:对资料进行初审,并查看每篇文献后的引文。纳入标准:文章所述内容应与间质干细胞及其免疫调节作用相关。排除标准:重复研究或Meta分析类文章。资料提炼:共收集到263篇相关文献,68篇文献符合纳入标准,排除的195篇文献为内容陈旧或重复。符合纳入标准的68篇文献中,分别涉及间质干细胞的免疫原性、免疫抑制作用及机制、应用等内容。资料综合:间质干细胞广泛存在于各种组织中,本身具有免疫原性低的特点,可以逃避同种异基因免疫识别。间质干细胞在体外、体内均有明确的免疫抑制作用,与间质干细胞对树突状细胞、T细胞、自然杀伤细胞等的调控作用有关。间质干细胞尚可对转化生长因子、白细胞介素、基质细胞来源因子、NF-κB配体、前列腺素、吲哚胺2,3-二氧酶等可溶性因子产生影响。由于间质干细胞多方面的免疫调节活性,使其拥有良好的应用前景,目前已在移植物抗宿主病及自身免疫疾病的治疗中发挥了作用。结论:间质干细胞无论在体内或体外均对T细胞的活化有抑制作用,可调节在同种异体抗原的识别和清除过程中主要细胞群的免疫功能,包括抗原递呈细胞、T细胞和自然杀伤细胞,但其调节免疫抑制作用的分子机制尚未被完全阐明。     

骨髓间充质干细胞防治多脏器衰竭

Objective The patients with lethal irradiation after sucessful hematopoietic stem cells transplan-tation had blood recovery, but did not avoid to died of multiple organ failure(MOF). To overcome the block, the article investigated mechanisms of mesenchymal stem cells (MSCs) protecting lethal radiated mice from multiple organ failure after haploid bone marrow cells transplantation. Method BALB/c mice irradiated with 8Gy60COγ-rays were randomly divided into two groups: MSCs group, infused MSCs labeled with cm-DiI and bone marrow monocytes of CB6F1 mice; Control group, only infused bone marrow monocytes; normal group, mice were infused cm-DiI marked MSCs without irradiation. The distribution of MSCs and the serous densities of Il-2, Il-10 and TNF-α in the recipients were observed after transplantation. Results MSCs collected in the bone marrow and the intes-tine in normal group at 15 d,in MSCs group MSCs enriched the different organs at 3,15 and 30 d. MSCs regulated down the secretion of IL-2 and TNF-α,and up the IL-10 density. Conclusions MSCs protected mice from multiple organ failure through above effects and may be open a new treatment strategy on acute radiation syndrome by stem cells.     

骨髓间充质干细胞防治多脏器衰竭

Objective The patients with lethal irradiation after sucessful hematopoietic stem cells transplan-tation had blood recovery, but did not avoid to died of multiple organ failure(MOF). To overcome the block, the article investigated mechanisms of mesenchymal stem cells (MSCs) protecting lethal radiated mice from multiple organ failure after haploid bone marrow cells transplantation. Method BALB/c mice irradiated with 8Gy60COγ-rays were randomly divided into two groups: MSCs group, infused MSCs labeled with cm-DiI and bone marrow monocytes of CB6F1 mice; Control group, only infused bone marrow monocytes; normal group, mice were infused cm-DiI marked MSCs without irradiation. The distribution of MSCs and the serous densities of Il-2, Il-10 and TNF-α in the recipients were observed after transplantation. Results MSCs collected in the bone marrow and the intes-tine in normal group at 15 d,in MSCs group MSCs enriched the different organs at 3,15 and 30 d. MSCs regulated down the secretion of IL-2 and TNF-α,and up the IL-10 density. Conclusions MSCs protected mice from multiple organ failure through above effects and may be open a new treatment strategy on acute radiation syndrome by stem cells.     

骨髓间充质干细胞防治多脏器衰竭

目的 探讨骨髓间充质干细胞(MSCs)防治半相合骨髓移植治疗致死剂量照射小鼠的多脏器衰竭(MOF)的作用及机制.方法 BALB/C小鼠8Gy60Coγ射线照射后,分为MSCs组,尾静脉输注经cm-Dil膜染剂标记的CB6F1小鼠的MSCs和骨髓细胞;对照组,只输注CB6F1骨髓细胞.正常组,不照射,输注标记的MSCs细胞.观察移植后不同时间,供者MSCs在受者体内分布,MSCs组和对照组小鼠外周血中IL-2,TNF-α和IL-10血清浓度变化情况.SAS 9.0软件对数据做成组t检验.结果 移植后15 d,正常组,MSCs主要集中在骨髓和小肠.MSC组,移植后不同时间,标记的细胞分别在胸腺、骨髓、小肠中富集.MSCs上调了IL-10的血清质量浓度,下调了IL-2和TNF-α的质量浓度,两组数据有统计学差异.结论 证实MSCs可以通过下调体内的促炎因子IL-2和TNF-α,及上调抑炎因子IL-10,抑制全身炎症反应综合征的发生,及MSCs体内多组织器官分布,发挥防治MOF的作用.     

间充质干细胞对睾丸辐射损伤的影响

目的:研究间充质干细胞(MSCs)对睾丸辐射损伤的影响,为临床上治疗放射性睾丸损伤奠定理论基础.方法:选取15只雄性SD大鼠随机分为对照组、模型组和治疗组.模型组和治疗组大鼠均接受直线加速器产生的高能电子线行一次性全身照射;对照组不接受照射.治疗组大鼠接受辐射24 h后尾静脉输注MSCs 3 × 106 /只;模型组和对照组大鼠尾静脉输注生理盐水1 mL;共3周.当模型组处于濒死状态时处死所有大鼠,检测各组大鼠血清中睾酮水平、血清和睾丸组织中丙二醛(MDA)含量及超氧化物歧化酶(SOD)活性;采用苏木精-伊红染色法 (HE染色法)制作大鼠的睾丸病理切片,观察辐射对睾丸形态学的影响.结果:模型组大鼠精神萎靡,反应迟钝,活动少,嗜睡,毛发变黄;治疗组大鼠较模型组反应灵敏.治疗组大鼠血清SOD明显高于模型组,而MDA水平低于模型组;治疗组大鼠血清睾酮含量明显高于模型组,但较正常组低.病理结果显示对照组生精小管横切面见精原细胞及不同发育阶段的精母细胞、精子细胞、精子,组成多种形态的完整生精上皮图像;模型组生精上皮变薄,生精层数减少,各级生精细胞明显减少,部分曲细精管内仅剩支持细胞和少量精原细胞,精子细胞及精子消失,显示辐射对大鼠睾丸组织损伤明显;治疗组外形较规则,各级生精细胞有序排列,初级精母细胞、精子细胞数量增多,精子发生良好,形态结构接近于对照组.结论:MSCs对睾丸的辐射损伤具有明显的修复作用,能够改善睾丸的生殖功能.     

骨髓间充质干细胞防治多脏器衰竭

Objective The patients with lethal irradiation after sucessful hematopoietic stem cells transplan-tation had blood recovery, but did not avoid to died of multiple organ failure(MOF). To overcome the block, the article investigated mechanisms of mesenchymal stem cells (MSCs) protecting lethal radiated mice from multiple organ failure after haploid bone marrow cells transplantation. Method BALB/c mice irradiated with 8Gy60COγ-rays were randomly divided into two groups: MSCs group, infused MSCs labeled with cm-DiI and bone marrow monocytes of CB6F1 mice; Control group, only infused bone marrow monocytes; normal group, mice were infused cm-DiI marked MSCs without irradiation. The distribution of MSCs and the serous densities of Il-2, Il-10 and TNF-α in the recipients were observed after transplantation. Results MSCs collected in the bone marrow and the intes-tine in normal group at 15 d,in MSCs group MSCs enriched the different organs at 3,15 and 30 d. MSCs regulated down the secretion of IL-2 and TNF-α,and up the IL-10 density. Conclusions MSCs protected mice from multiple organ failure through above effects and may be open a new treatment strategy on acute radiation syndrome by stem cells.     

Mesenchymal stem cells and acute lung injury

Acute respiratory distress syndrome (ARDS) is a clinical syndrome of acute respiratory failure presenting with hypoxemia and bilateral pulmonary infiltrates, most often in the setting of pneumonia, sepsis, or major trauma. The pathogenesis of ARDS involves lung endothelial injury, alveolar epithelial injury, and the accumulation of protein-rich fluid and cellular debris in the alveolar space. No pharmacologic therapy has so far proved effective. A potential strategy involves cell-based therapies, including mesenchymal stem cells (MSCs). Herein we review basic properties of MSCs, their use in preclinical models of lung injury and ARDS, and potential therapeutic mechanisms.     

骨髓间充质干细胞防治多脏器衰竭

Objective The patients with lethal irradiation after sucessful hematopoietic stem cells transplan-tation had blood recovery, but did not avoid to died of multiple organ failure(MOF). To overcome the block, the article investigated mechanisms of mesenchymal stem cells (MSCs) protecting lethal radiated mice from multiple organ failure after haploid bone marrow cells transplantation. Method BALB/c mice irradiated with 8Gy60COγ-rays were randomly divided into two groups: MSCs group, infused MSCs labeled with cm-DiI and bone marrow monocytes of CB6F1 mice; Control group, only infused bone marrow monocytes; normal group, mice were infused cm-DiI marked MSCs without irradiation. The distribution of MSCs and the serous densities of Il-2, Il-10 and TNF-α in the recipients were observed after transplantation. Results MSCs collected in the bone marrow and the intes-tine in normal group at 15 d,in MSCs group MSCs enriched the different organs at 3,15 and 30 d. MSCs regulated down the secretion of IL-2 and TNF-α,and up the IL-10 density. Conclusions MSCs protected mice from multiple organ failure through above effects and may be open a new treatment strategy on acute radiation syndrome by stem cells.     

骨髓间充质干细胞防治多脏器衰竭

Objective The patients with lethal irradiation after sucessful hematopoietic stem cells transplan-tation had blood recovery, but did not avoid to died of multiple organ failure(MOF). To overcome the block, the article investigated mechanisms of mesenchymal stem cells (MSCs) protecting lethal radiated mice from multiple organ failure after haploid bone marrow cells transplantation. Method BALB/c mice irradiated with 8Gy60COγ-rays were randomly divided into two groups: MSCs group, infused MSCs labeled with cm-DiI and bone marrow monocytes of CB6F1 mice; Control group, only infused bone marrow monocytes; normal group, mice were infused cm-DiI marked MSCs without irradiation. The distribution of MSCs and the serous densities of Il-2, Il-10 and TNF-α in the recipients were observed after transplantation. Results MSCs collected in the bone marrow and the intes-tine in normal group at 15 d,in MSCs group MSCs enriched the different organs at 3,15 and 30 d. MSCs regulated down the secretion of IL-2 and TNF-α,and up the IL-10 density. Conclusions MSCs protected mice from multiple organ failure through above effects and may be open a new treatment strategy on acute radiation syndrome by stem cells.     

骨髓间充质干细胞防治多脏器衰竭

Objective The patients with lethal irradiation after sucessful hematopoietic stem cells transplan-tation had blood recovery, but did not avoid to died of multiple organ failure(MOF). To overcome the block, the article investigated mechanisms of mesenchymal stem cells (MSCs) protecting lethal radiated mice from multiple organ failure after haploid bone marrow cells transplantation. Method BALB/c mice irradiated with 8Gy60COγ-rays were randomly divided into two groups: MSCs group, infused MSCs labeled with cm-DiI and bone marrow monocytes of CB6F1 mice; Control group, only infused bone marrow monocytes; normal group, mice were infused cm-DiI marked MSCs without irradiation. The distribution of MSCs and the serous densities of Il-2, Il-10 and TNF-α in the recipients were observed after transplantation. Results MSCs collected in the bone marrow and the intes-tine in normal group at 15 d,in MSCs group MSCs enriched the different organs at 3,15 and 30 d. MSCs regulated down the secretion of IL-2 and TNF-α,and up the IL-10 density. Conclusions MSCs protected mice from multiple organ failure through above effects and may be open a new treatment strategy on acute radiation syndrome by stem cells.     

骨髓间充质干细胞防治多脏器衰竭

Objective The patients with lethal irradiation after sucessful hematopoietic stem cells transplan-tation had blood recovery, but did not avoid to died of multiple organ failure(MOF). To overcome the block, the article investigated mechanisms of mesenchymal stem cells (MSCs) protecting lethal radiated mice from multiple organ failure after haploid bone marrow cells transplantation. Method BALB/c mice irradiated with 8Gy60COγ-rays were randomly divided into two groups: MSCs group, infused MSCs labeled with cm-DiI and bone marrow monocytes of CB6F1 mice; Control group, only infused bone marrow monocytes; normal group, mice were infused cm-DiI marked MSCs without irradiation. The distribution of MSCs and the serous densities of Il-2, Il-10 and TNF-α in the recipients were observed after transplantation. Results MSCs collected in the bone marrow and the intes-tine in normal group at 15 d,in MSCs group MSCs enriched the different organs at 3,15 and 30 d. MSCs regulated down the secretion of IL-2 and TNF-α,and up the IL-10 density. Conclusions MSCs protected mice from multiple organ failure through above effects and may be open a new treatment strategy on acute radiation syndrome by stem cells.     

骨髓间充质干细胞防治多脏器衰竭

Objective The patients with lethal irradiation after sucessful hematopoietic stem cells transplan-tation had blood recovery, but did not avoid to died of multiple organ failure(MOF). To overcome the block, the article investigated mechanisms of mesenchymal stem cells (MSCs) protecting lethal radiated mice from multiple organ failure after haploid bone marrow cells transplantation. Method BALB/c mice irradiated with 8Gy60COγ-rays were randomly divided into two groups: MSCs group, infused MSCs labeled with cm-DiI and bone marrow monocytes of CB6F1 mice; Control group, only infused bone marrow monocytes; normal group, mice were infused cm-DiI marked MSCs without irradiation. The distribution of MSCs and the serous densities of Il-2, Il-10 and TNF-α in the recipients were observed after transplantation. Results MSCs collected in the bone marrow and the intes-tine in normal group at 15 d,in MSCs group MSCs enriched the different organs at 3,15 and 30 d. MSCs regulated down the secretion of IL-2 and TNF-α,and up the IL-10 density. Conclusions MSCs protected mice from multiple organ failure through above effects and may be open a new treatment strategy on acute radiation syndrome by stem cells.     

骨髓间充质干细胞防治多脏器衰竭

Objective The patients with lethal irradiation after sucessful hematopoietic stem cells transplan-tation had blood recovery, but did not avoid to died of multiple organ failure(MOF). To overcome the block, the article investigated mechanisms of mesenchymal stem cells (MSCs) protecting lethal radiated mice from multiple organ failure after haploid bone marrow cells transplantation. Method BALB/c mice irradiated with 8Gy60COγ-rays were randomly divided into two groups: MSCs group, infused MSCs labeled with cm-DiI and bone marrow monocytes of CB6F1 mice; Control group, only infused bone marrow monocytes; normal group, mice were infused cm-DiI marked MSCs without irradiation. The distribution of MSCs and the serous densities of Il-2, Il-10 and TNF-α in the recipients were observed after transplantation. Results MSCs collected in the bone marrow and the intes-tine in normal group at 15 d,in MSCs group MSCs enriched the different organs at 3,15 and 30 d. MSCs regulated down the secretion of IL-2 and TNF-α,and up the IL-10 density. Conclusions MSCs protected mice from multiple organ failure through above effects and may be open a new treatment strategy on acute radiation syndrome by stem cells.     

Mesenchymal stem cells for cardiac cell therapy

Despite refinements of medical and surgical therapies, heart failure remains a fatal disease. Myocardial infarction is the most common cause of heart failure, and only palliative measures are available to relieve symptoms and prolong the patient's life span. Because mammalian cardiomyocytes irreversibly exit the cell cycle at about the time of birth, the heart has traditionally been considered to lack any regenerative capacity. This paradigm, however, is currently shifting, and the cellular composition of the myocardium is being targeted by various regeneration strategies. Adult progenitor and stem cell treatment of diseased human myocardium has been carried out for more than 10 years (Menasche et al., 2001; Stamm et al., 2003), and it has become clear that, in humans, the regenerative capacity of hematopoietic stem cells and endothelial progenitor cells, despite potent proangiogenic effects, is limited (Stamm et al., 2009). More recently, mesenchymal stem cells (MSCs) and related cell types are being evaluated in preclinical models of heart disease as well as in clinical trials (see Published Clinical Trials, below). MSCs have the capacity to self-renew and to differentiate into lineages that normally originate from the embryonic mesenchyme (connective tissues, blood vessels, blood-related organs) (Caplan, 1991; Prockop, 1997; Pittenger et al., 1999). The current definition of MSCs includes plastic adherence in cell culture, specific surface antigen expression (CD105(+)/CD90(+)/CD73(+), CD34(-)/CD45(-)/CD11b(-) or CD14(-)/CD19(-) or CD79α(-)/HLA-DR1(-)), and multilineage in vitro differentiation potential (osteogenic, chondrogenic, and adipogenic) (Dominici et al., 2006 ). If those criteria are not met completely, the term "mesenchymal stromal cells" should be used for marrow-derived adherent cells, or other terms for MSC-like cells of different origin. For the purpose of this review, MSCs and related cells are discussed in general, and cell type-specific properties are indicated when appropriate. We first summarize the preclinical data on MSCs in models of heart disease, and then appraise the clinical experience with MSCs for cardiac cell therapy.     

骨髓间充质干细胞防治多脏器衰竭

Objective The patients with lethal irradiation after sucessful hematopoietic stem cells transplan-tation had blood recovery, but did not avoid to died of multiple organ failure(MOF). To overcome the block, the article investigated mechanisms of mesenchymal stem cells (MSCs) protecting lethal radiated mice from multiple organ failure after haploid bone marrow cells transplantation. Method BALB/c mice irradiated with 8Gy60COγ-rays were randomly divided into two groups: MSCs group, infused MSCs labeled with cm-DiI and bone marrow monocytes of CB6F1 mice; Control group, only infused bone marrow monocytes; normal group, mice were infused cm-DiI marked MSCs without irradiation. The distribution of MSCs and the serous densities of Il-2, Il-10 and TNF-α in the recipients were observed after transplantation. Results MSCs collected in the bone marrow and the intes-tine in normal group at 15 d,in MSCs group MSCs enriched the different organs at 3,15 and 30 d. MSCs regulated down the secretion of IL-2 and TNF-α,and up the IL-10 density. Conclusions MSCs protected mice from multiple organ failure through above effects and may be open a new treatment strategy on acute radiation syndrome by stem cells.     

间充质干细胞治疗脊髓小脑性共济失调

背景：脊髓小脑性共济失调是临床上较常见的以进行性加重的四肢共济运动障碍为主要临床表现的中枢神经系统变性疾病,常规药物治疗效果欠佳。目的：观察自体骨髓间充质干细胞以及异体脐带间充质干细胞输注治疗脊髓小脑性共济失调的临床效果。方法：对接受间充质干细胞治疗的27例确诊脊髓小脑性共济失调患者进行综合统计分析,其中6例行自体骨髓间充质干细胞腰穿治疗,21例行异体脐带间充质干细胞腰穿结合静脉输注治疗,两组患者均采用世界神经病联合会国际合作共济失调量表（International Cooperative Ataxia Rating Scale,ICARS）对患者治疗前后神经功能进行评定。结果与结论：所有27例脊髓小脑共济失调患者行间充质干细胞治疗过程中以及治疗前后均未及明显不良反应。其中6例患者采用自体骨髓间充质干细胞治疗后效果均不明显,另外21例患者行异体脐带间充质干细胞输注治疗,治疗后3个月与治疗前比较,患者自觉症状均有一定程度改善,ICARS评分明显降低（P〈0．05）。说明脐带间充质干细胞治疗是安全的,可以一定程度地改善脊髓小脑性共济失调患者的临床症状,提高患者生活质量。     

脐血间质干细胞:神经干细胞的新来源

目的:脐血间质干细胞经诱导分化为神经干细胞的方法,已成为近来细胞移植治疗中枢神经系统疾病研究的热点问题。资料来源:应用计算机检索Medline1994-01/2004-08以及NCBI1994-01/2004-08期间的关于脐血间质干细胞与神经干细胞的文章,检索词“humanumbilicalcordbloodmesenchymalstemcells,neuralstemcells,并限定语言种类为English。同时计算机检索中文数据库CNKI1994-01/2004-08期间的相关文章,检索词“脐血,间质干细胞,神经干细胞”。资料选择:对资料进行初审,选取有关中分离脐血间质干细胞,诱导分化为神经细胞的相关实验研究,及脐血细胞移植治疗中枢神经系统疾病方面的论著。资料提炼:共收集到关于脐血脐血间质干细胞诱导分化为神经细胞及用于细胞移植治疗中枢神经系统疾病的文献37篇,中文4篇,英文33篇。资料综合:神经干细胞移植已被用于促进神经系统疾病的修复,但神经干细胞的来源十分有限。脐血间质干细胞是中胚层发育的早期细胞,有多向分化潜能,可以通过骨髓、脐血和周围血获得。脐血间质干细胞在适宜的体内或体外环境下,可分化为神经元及神经胶质细胞,并在分化过程中表达神经干细胞特异性标志。加之脐血来源丰富,采集方便,免疫排斥反应低,使脐血间质干细胞成为用于细胞移植治疗神经系统疾患的又一     

间充质干细胞治疗类风湿性关节炎的研究与应用

背景：目前的研究发现来源于骨髓或脂肪组织的间充质干细胞具有免疫抑制及抗炎的特性,使得其在治疗类风湿性关节炎等自身免疫性疾病方面具有广阔的应用前景。目的：综述间充质干细胞的生物学特性、特别是免疫抑制及抗炎作用机制及其在治疗类风湿性关节炎方面的研究进展。方法：检索2005/2011西文生物医学期刊文献数据及CNKI数据库有关类风湿性关节炎研究、骨髓间充质干细胞生物学特性及其免疫抑制作用、在类风湿性关节炎方面的应用方面的文献,英文检索词为＂marrowstemcells,rheumatoidarthritis,immunosuppressive＂,中文检索词为＂间充质干细胞,类风湿性关节炎,免疫抑制＂,纳入近年来起重大影响以及开启和引领新方向的重要研究成果,排除重复性研究,纳入24篇文章进行综述。结果与结论：间充质干细胞在维持关节组织的内环境稳态,如调控炎症反应及免疫应答、抗纤维化及组织再生方面具有重要的作用,而间充质干细胞在治疗类风湿性关节炎方面疗效的稳定性及安全性方面仍需进一步的研究。     

Mesenchymal stem cells: biological properties and clinical applications

Importance of the field: In the last decade, knowledge of mesenchymal stem cells (MSCs) has evolved rapidly; their immunomodulatory properties and paracrine interactions with specific cell types in damaged tissues and promising results in some clinical applications have made these cells an attractive option for the treatment of certain diseases.

Areas covered in this review: We present some relevant methodological issues and biological properties of MSCs, as well as clinical applications of MSC therapies with particular emphasis in the treatment of graft versus host disease (GVHD), complex perianal fistula and refractory metastatic neuroblastoma. Other topical aspects relevant to the application of cellular therapies such as biosafety studies and cellular production of MSCs are also discussed in this review.

What the reader will gain: The growing optimism regarding MSCs research is based on the promising results obtained in in vitro and in vivo studies. The rapid translational research with MSCs necessitated standardization of methodology and terminology and greater focus on other aspects such as biosafety and cellular production, especially for clinical use of MSCs.

Take home message: Much has been learned about the biology and applications of MSCs and much remains to be learned.