人脐带间充质干细胞微囊减轻小鼠急性肾损伤的研究

目的探讨人脐带间充质干细胞（MSCs）源性细胞外囊泡Oct-4 mRNA对受损的肾小管上皮细胞修复的作用及相关机制。 方法将培养的缺氧损伤肾小管上皮细胞置于含有人脐带MSCs细胞外囊泡及不同对照培养液的培养腔室玻片上孵育48?h,应用BrdU及TUNEL染色,检测各组细胞增殖或凋亡情况。将急性肾损伤模型小鼠分为4组：空白组、EVs组、Oct-4过表达组、Oct-4低敲组。并按照分组分别注射磷酸盐缓冲液（Vehicle）,人脐带MSCs细胞外囊泡（EVs）,过表达Oct-4基因的人脐带MSCs细胞外囊泡（EVs?+?Oct-4）及敲除Oct-4基因的人脐带MSCs外囊泡（EVs-Oct-4）,并在注射48?h及2周后采血测肌酐（Crea）及尿素氮（BUN）,了解肾功能变化;对各组上述处理后的肾组织应用TUNEL与增殖细胞核抗原表达量检测各组肾脏细胞凋亡与增殖情况;通过Masson染色检测了各组肾脏纤维化程度;通过PCR探索肾损伤后肾组织细胞Snail基因的表达变化。数据分析采用方差分析和SNK-q检验。 结果EVs?+ Oct-4处理缺氧的肾小管上皮细胞48?h后,TUNEL染色显示具有最少的凋亡细胞数（0~1）/?HPF,BrdU显示有最多的增殖细胞（7±2）/HPF。EVs,EV-Oct-4以及Vehicle对体外缺氧肾小管上皮细胞的上述作用依次减弱（P?相似文献   

间充质干细胞移植治疗急性肺损伤的研究进展

急性肺损伤是一种临床常见的危重病症,临床上传统的治疗方法一般以尽早去除诱因、控制感染、机械通气及器官功能支持治疗为主。间充质干细胞属于成体干细胞的一种,能主动归巢至肺损伤部位,并通过向肺泡和支气管上皮细胞分化参与组织修复,同时间充质干细胞能够调节急性肺损伤时局部和全身炎症反应和免疫紊乱,从而发挥治疗作用,可能是治疗急性肺损伤的一个很有前景的方法。作者就间充质干细胞移植治疗急性肺损伤的研究进展进行综述。     

WJSC 6th Anniversary Special Issues（2）:Mesenchymal stem cells Enhancing the efficacy of mesenchymal stem cell therapy

Mesenchymal stem cell(MSC)therapy is entering a challenging phase after completion of many preclinical and clinical trials.Among the major hurdles encountered in MSC therapy are inconsistent stem cell potency,poor cell engraftment and survival,and age/disease-related host tissue impairment.The recognition that MSCs primarily mediate therapeutic benefits through paracrine mechanisms independent of cell differentiation provides a promising framework for enhancing stem cell potency and therapeutic benefits.Several MSC priming approaches are highlighted,which will likely allow us to harness the full potential of adult stem cells for their future routine clinical use.     

Bone-derived mesenchymal stromal cells from HIV transgenic mice exhibit altered proliferation,differentiation capacity and paracrine functions along with impaired therapeutic potential in kidney injury

Mesenchymal stem cells (MSCs) secrete paracrine factors that could be cytoprotective and serve roles in immunoregulation during tissue injury. Although MSCs express HIV receptors, and co-receptors, and are susceptible to HIV infection, whether HIV-1 may affect biological properties of MSCs needs more study. We evaluated cellular proliferation, differentiation and paracrine functions of MSCs isolated from compact bones of healthy control mice and Tg26 HIV-1 transgenic mice. The ability of MSCs to protect against cisplatin toxicity was studied in cultured renal tubular cells as well as in intact mice. We successfully isolated MSCs from healthy mice and Tg26 HIV-1 transgenic mice and found the latter expressed viral Nef, Vpu, NL4-3 and Vif genes. The proliferation and differentiation of Tg26 HIV-1 MSCs was inferior to MSCs from healthy mice. Moreover, transplantation of Tg26 HIV-1 MSCs less effectively improved outcomes compared with healthy MSCs in mice with acute kidney injury. Also, Tg26 HIV-1 MSCs secreted multiple cytokines, but at significantly lower levels than healthy MSCs, which resulted in failure of conditioned medium from these MSCs to protect cultured renal tubular cells from cisplatin toxicity. Therefore, HIV-1 had adverse biological effects on MSCs extending to their proliferation, differentiation, function, and therapeutic potential. These findings will help in advancing mechanistical insight in renal injury and repair in the setting of HIV-1 infection.     

间充质干细胞旁分泌作用的研究进展

间充质干细胞（MSCs）通常利用多分化特性在组织损伤时起到修复功能。然而,近期研究表明,MSCs大多数治疗作用都是通过旁分泌来发挥作用的,其中最受关注的是可溶性蛋白分泌和细胞外膜泡（EVS）。MSCs释放的EVS可反映细胞的来源,能够影响局部微环境中其他细胞的活动。越来越多人提出利用MSCs分泌的各种因子（称为分泌体）替代MSCs细胞治疗的观点。现就MSCs旁分泌特性、分泌体发生和释放机制以及细胞来源对旁分泌影响等方面的研究进展进行综述。     

Cellular senescence,a novel therapeutic target for mesenchymal stem cells in acute kidney injury

Cellular senescence is a widespread cellular programme that is characterized by permanent cell cycle arrest. Senescent cells adopt a changed secretory phenotype that can alter cellular function. For years, cellular senescence has been thought to be a protective factor against cancer; however, it is now recognized that it has a dual effect on individuals. Co-ordinated activation of cellular senescence provides advantages during embryogenesis, wound healing, tissue repair and inhibition of tumorigenesis. On the other hand, the aberrant generation and accumulation of abnormal senescent cells lead to the development of age-related conditions and tissue deterioration. During acute kidney injury (AKI), the kidney faces multiple types of stressors and challenges, which can easily drive cellular senescence. How to appropriately progress through the cell cycle and minimize long-term damage is of great importance to the acquisition of adaptive repair considering that no available therapeutic interventions can reliably limit injury, speedy recovery or improve the prognosis of this syndrome. Whether the manipulation of cellular senescence can become a novel therapeutic target in AKI and reignite clinical and research interest remains to be determined. Here, we share our current understanding of the role of cellular senescence in AKI, along with examples of the application of mesenchymal stem cells (MSCs) for targeting this disorder during its treatment.     

Potential therapeutic applications of mesenchymal stem cells for the treatment of eye diseases

Stem cell-based treatments have been extensively explored in the last few decades to develop therapeutic strategies aimed at providing effective alternatives for those human pathologies in which surgical or pharmacological therapies produce limited effects. Among stem cells of different sources, mesenchymal stem cells (MSCs) offer several advantages, such as the absence of ethical concerns, easy harvesting, low immunogenicity and reduced tumorigenesis risks. Other than a multipotent differentiation ability, MSCs can release extracellular vesicles conveying proteins, mRNA and microRNA. Thanks to these properties, new therapeutic approaches have been designed for the treatment of various pathologies, including ocular diseases. In this review, the use of different MSCs and different administration strategies are described for the treatment of diabetic retinopathy, glaucoma, and retinitis pigmentosa. In a large number of investigations, positive results have been obtained by in vitro experiments and by MSC administration in animal models. Most authors agree that beneficial effects are likely related to MSC paracrine activity. Based on these considerations, many clinical trials have already been carried out. Overall, although some adverse effects have been described, promising outcomes are reported. It can be assumed that in the near future, safer and more effective protocols will be developed for more numerous clinical applications to improve the quality of life of patients affected by eye diseases.     

Application of mesenchymal stem cells derived from human pluripotent stem cells in regenerative medicine

Mesenchymal stem cells (MSCs) represent the most clinically used stem cells in regenerative medicine. However, due to the disadvantages with primary MSCs, such as limited cell proliferative capacity and rarity in the tissues leading to limited MSCs, gradual loss of differentiation during in vitro expansion reducing the efficacy of MSC application, and variation among donors increasing the uncertainty of MSC efficacy, the clinical application of MSCs has been greatly hampered. MSCs derived from human pluripotent stem cells (hPSC-MSCs) can circumvent these problems associated with primary MSCs. Due to the infinite self-renewal of hPSCs and their differentiation potential towards MSCs, hPSC-MSCs are emerging as an attractive alternative for regenerative medicine. This review summarizes the progress on derivation of MSCs from human pluripotent stem cells, disease modelling and drug screening using hPSC-MSCs, and various applications of hPSC-MSCs in regenerative medicine. In the end, the challenges and concerns with hPSC-MSC applications are also discussed.     

Uncovering the secretes of mesenchymal stem cells

Mesenchymal stem cells (MSC) show great promise in a wide array of therapeutic applications due mainly to their capacity to suppress immune and inflammatory reactions and instigate normal tissue repair processes. The secretion of bioactive factors is thought to play a predominant role in the mechanisms of action for these clinically relevant functions. As such, a large body of MSC research has focussed on characterization of the MSC secretome; including both soluble factors and factors released in extracellular vesicles (e.g., exosomes and microvesicles). This review provides an overview of our current knowledge of the MSC secretome in the context of determining the clinical relevance of these cells. In addition, the review summarizes various approaches that have been utilized to identify proteins secreted by MSC and discusses the advantages and limitations of different proteomic methods. Finally, we discuss issues that must be addressed before the clinical relevance of research into the MSC secretome can be realized.     

骨髓间质干细胞修复受损心肌研究进展

骨髓间充质干细胞是一种多潜能干细胞。在体外培养时,多种诱导因素可使其分化为心肌细胞等。目前进行的动物实验和临床研究表明骨髓间充质干细胞具有促进血管增生以及改善心肌梗死后心脏功能的作用,为受损心肌的治疗提供了广阔前景。但是其修复受损心肌的机制仍具有很大争议。本文就以上内容进行综述。     

Back to the future: moving beyond "mesenchymal stem cells"

The last decade was dominated by dissemination of the notion that postnatal "mesenchymal stem cells," found primarily in bone marrow but also in other tissues, can generate multiple skeletal and nonskeletal tissues, and thus can be exploited to regenerate a broad range of tissues and organs. The concept of "mesenchymal stem cells" and its applicative implications represent a significant departure from the solidly proven notion that skeletal stem cells are found in the bone marrow (and not in other tissues). Recent data that sharpen our understanding of the identity, nature, origin, and in vivo function of the archetypal "mesenchymal stem cells" (bone marrow skeletal stem cells) point to their microvascular location, mural cell identity, and function as organizers and regulators of the hematopoietic microenvironment/niche. These advances bring back the original concept from which the notion of "mesenchymal stem cells" evolved, and clarify a great deal of experimental data that accumulated in the past decade. As a novel paradigm emerges that accounts for many facets of the biology of skeletal stem cells, a novel paradigm independently emerges for their applicative/translational use. The two paradigms meet each other back in the future.     

间充质干细胞基础研究与临床转化的中美比较

目的：从基础研究、专利申请、临床试验角度对比分析中美间充质干细胞领域发展现状和趋势,了解中美间充质干细胞领域研究的主要特征,为中国间充质干细胞领域的发展提供建议。方法：检索SCI论文数据、DII专利数据及Clinical Trials临床试验数据及新药审批情况,利用Excel、DDA工具对检索结果进行定量分析和讨论。结果：中国在间充质干细胞基础研究、专利申请及临床试验方面虽起步较晚,但近年来发展迅速,论文、专利和临床试验数量快速增长,2014年起发表论文数量及2016年申请专利数量均超过美国,临床试验注册已达200余项;在骨质疏松、脊髓损伤等研究领域,内分泌系统疾病、自体免疫疾病等临床试验方面形成一定优势,已具备坚实的团队与技术基础。但我国间充质干细胞研究仍面临激烈的竞争,存在进步与发展空间。结论：我国间充质干细胞研究应发挥已有优势,加强战略性布局;重视发展以企业为主导的新药开发路径;做精做细以增强国际竞争力与影响力;加大资金投入和产业政策的支持;健全监管机制及评价体系,抓住机遇的同时积极迎接挑战。     

Biological,chemical and mechanical factors regulating migration and homing of mesenchymal stem cells

Mesenchymal stem cells (MSCs) are a population of primary and non-specialized cells, which can be isolated from various tissues. Currently, MSCs are key players in cellular therapy and regenerative medicine. However, the possibility of using MSCs in the treatment of many diseases needs to be preceded, though, by in-depth analysis of their properties, especially by determining the mechanism of tissue homing as well as the mechanism, due to which cells contribute to tissue regeneration. This review is intended to present information on recent findings regarding the mechanism of recruitment and tissue homing by MSCs and discuss current hypotheses for how MSCs can reach target tissues.     

Preconditioning strategies for improving the survival rate and paracrine ability of mesenchymal stem cells in acute kidney injury

Acute kidney injury (AKI) is a common, severe emergency case in clinics, with high incidence, significant mortality and increased costs. Despite development in the understanding of its pathophysiology, the therapeutic choices are still confined to dialysis and renal transplantation. Considering their antiapoptotic, immunomodulatory, antioxidative and pro‐angiogenic effects, mesenchymal stem cells (MSCs) may be a promising candidate for AKI management. Based on these findings, some clinical trials have been performed, but the results are contradictory (NCT00733876, NCT01602328). The low engraftment, poor survival rate, impaired paracrine ability and delayed administration of MSCs are the four main reasons for the limited clinical efficacy. Investigators have developed a series of preconditioning strategies to improve MSC survival rates and paracrine ability. In this review, by summarizing these encouraging studies, we intend to provide a comprehensive understanding of various preconditioning strategies on AKI therapy and improve the prognosis of AKI patients by regenerative medicine.     

Mesenchymal stem cells in ischemic tissue regeneration

Diseases caused by ischemia are one of the leading causes of death in the world. Current therapies for treating acute myocardial infarction, ischemic stroke, and critical limb ischemia do not complete recovery. Regenerative therapies opens new therapeutic strategy in the treatment of ischemic disorders. Mesenchymal stem cells(MSCs) are the most promising option in the field of cell-based therapies, due to their secretory and immunomodulatory abilities, that contribute to ease inflammation and pr...     

Diet composition transiently modulates proliferative and potency features of human cord blood-derived mesenchymal stem cells

Mesenchymal stem cells (MSC) emerged in the last few years as a promise in regenerative medicine and have been actively tested in several clinical trials worldwide. However, the lack of common standards and a precise definition of MSC preparations remain a major obstacle in research and application. In this study, we compared the effects during culture of two different MSC commercial media (aMEM and SPE-IV) on the proliferative capacities, phenotypic and molecular features in human cord blood derived-MSC lines. Moreover, as miRNA are markers of stem cell multipotency and regulators of somatic cell reprogramming, we performed a miRNome analysis in both conditions. As a result, we observed that SPE-IV promoted a faster growth and modulated stemness and proliferation associated genes such as PDGFRB, p16 and p21. Notably, in aMEM miR-335 and miR-302b, both proposed as putative stemness markers, were upregulated together with miRNAs reported to decrease adipo- and osteogenesis confirming the observed reduced differentiation potential after growth in this condition. Intriguingly, phenotypic divergences were entirely due to culturing conditions and, most importantly, completely transitory since, after medium switch, the cells were able to revert their signatures. Thus, it emerges as crucial keeping constant the experimental settings, starting from culturing conditions, to avoid misleading characterization of stemness and/or potency markers when the eventual goal is unequivocal definition of such parameters for future clinical choice.     

Alleviation of apoptosis of bone marrow-derived mesenchymal stem cells in the acute injured kidney by heme oxygenase-1 gene modification

Bone marrow-derived mesenchymal stem cells (BMSCs) transplantation is beneficial for the treatment of acute kidney injury (AKI), but the poor survival of BMSCs limits the repair effect. The oxidative stress in the AKI microenvironment is regarded as the main reason. Considering the potent anti-oxidant ability of heme oxygenase-1 (HO-1), HO-1 overexpression in BMSCs can be expected to improve the survival of BMSCs and correspondingly enhance the AKI repair effect. Here, BMSCs are transfected with pLV-HO-1/eGFP and pLV–eGFP by the lentivirus vector to get HO-1-BMSCs and eGFP-BMSCs, respectively. Ischemia/reperfusion-AKI kidney homogenate supernatant (KHS) is prepared for treating BMSCs, eGFP-BMSCs and HO-1-BMSCs. AKI-KHS results in a high inhibitory rate of BMSCs growth and a high proportion of TUNEL positive BMSCs, while HO-1 overexpression inverses this phenomenon and re-establishes the antioxidant and oxidant balance in HO-1-BMSCs. Phosphorylations of p53 and p38 mitogen-activated protein kinases (p38 MAPK) in HO-1-BMSCs decrease. Lower levels of monocyte chemotactic protein 1, tumor necrosis factor-α and interleukin 1β are also observed in supernatant of HO-1-BMSCs. The in vivo study shows that HO-1 overexpression sharply decreases the apoptosis of BMSCs in the injured kidney, and correspondingly the renal function of the AKI rats improves significantly. In conclusion, BMSCs with HO-1 overexpression suggests a better survival in the I/R-AKI microenvironment and a better kidney repair effect. The anti-oxidant effect via the inactivations of the downstream p53 and p38MAPK in BMSCs and the anti-inflammation could be the mechanisms. It provides a novel approach for the cell-based AKI-therapy.     

Molecular markers distinguish bone marrow mesenchymal stem cells from fibroblasts

To characterize mesenchymal stem cells (MSC), we compared gene expression profiles in human bone marrow MSC (11 lines) and human fibroblasts (4 lines) by RT-PCR and real time PCR. Messenger RNA levels of MHC-DR-alpha, MHC-DR-beta, MHC-DR-associated protein CD74, tissue factor pathway inhibitor-2, and neuroserpin were much higher in MSC than in fibroblasts, even in the presence of large interindividual variations. Those of adrenomedullin, apolipoprotein D, C-type lectin superfamily member-2, collagen type XV alpha1, CUG triplet repeat RNA-binding protein, matrix metalloproteinase-1, protein tyrosine kinase-7, and Sam68-like phosphotyrosine protein/T-STAR were lower in MSC than in fibroblasts. FACS analysis showed that cell surface expression of MHC-DR was also higher in MSC than in fibroblasts. MHC-DR expression decreased after osteogenic differentiation, whereas the expression of adrenomedullin-a potent stimulator of osteoblast activity-along with collagen XV alpha1 and apolipoprotein D increased after osteogenic differentiation. The marker genes identified in this study should be useful for characterization of MSC both in basic and clinical studies.     

间充质干细胞对新型冠状病毒肺炎免疫损伤潜在修复作用的研究进展

针对新型冠状病毒肆虐以及暂无特效药物治疗的情况,多地已开展间充质干细胞(MSCs)在新型冠状病毒感染重症救治方面的临床研究,在规范应用的前提下,经过严格的临床检验后,对若干重型患者进行治疗并取得了一定效果。MSCs能抑制免疫系统过度激活,通过改善微环境促进内源性修复、抑制肺部炎症的进展达到缓解呼吸窘迫症状的目的。本文就新型冠状病毒免疫损伤的发生机制、治疗现状以及MSCs在治疗新型冠状病毒感染的潜在治疗机制作一介绍。