释放膜微粒：间充质干细胞治疗的新机制

间充质干细胞（Mesenchymalstemcells,MSC）是一类具有自我更新和多向分化潜能的成体干细胞,具有取材方便、体外扩增能力强和免疫原性低等特点,已成为细胞治疗和组织工程的重要种子细胞。MSC治疗已经进入临床试验阶段,部分疾病已经完成Ⅲ期临床试验,证实了这种新型疗法的安全性和有效性。然而．关于MSC治疗的机制并未阐明。近几年的研究发现,间充质干细胞的分化及其旁分泌作用,可能不是其组织修复及治疗多种疾病的主要原因．而来源于间充质干细胞的膜微粒,可能是治疗过程中的主要参与者。本文就MSC膜微粒的生物学特性、作用机制及临床应用的可能性等问题进行综述。     

骨髓间充质干细胞减轻体外扩增的脐血造血干细胞衰老的作用

目的 探讨骨髓间充质干细胞(MSC)对脐血造血干细胞体外扩增及抗细胞衰老的作用.方法 从新鲜脐血中分离出CD34+细胞,分别接种在含或不含MSC及细胞因子的培养体系中,取培养10d后的造血干细胞,分别用于细胞计数,集落分析,流式细胞仪检测表面标记,并对培养后的细胞进行β-半乳糖苷酶活性检测,采用实时定量聚合酶链反应(PCR)检测衰老相关基因p16INK4amRNA的表达.结果 体外培养10d后,MSC组、细胞因子组及MSC+细胞因子组对脐血总有核细胞(TNC)、CD34+细胞的体外扩增及克隆形成能力均有支持作用,以MSC+细胞因子组最为明显(P＜0.05),其扩增倍数分别达到(45.3±6.8)倍、(38.4±5.8)倍及(50.2±4.2)倍,但衰老细胞比例及p16INK4amRNA表达倍数则以MSC组最低,MSC+细胞因子组次之,细胞因子组两项指标均为最高(P＜0.05).结论 MSC能更好保护体外扩增的脐血造血干细胞,减少细胞衰老的发生,MSC+细胞因子是有效扩增脐血造血干细胞并保持细胞干性的更理想方法.     

异基因外周血造血干细胞和脐带血间充质干细胞联合移植治疗肝炎后重型再生障碍性贫血一例

间充质干细胞(MSC)是造血微环境的重要组成部分,具有促进造血细胞归巢、减低移植物抗宿主病(GVHD)的发生等作用.我院于2009年采用异基因外周血造血干细胞和脐带血MSC联合移植治疗肝炎相关性重型再生障碍性贫血(HAAA)1例,疗效满意,现报道如下.     

间充质干细胞治疗激素耐药的重度急性移植物抗宿主病的Ⅱ期临床研究

重度移植物抗宿主病(GVHD)是异基因造血干细胞移植的致命性并发症,糖皮质激素是急性GVHD的一线治疗药物,但激素治疗的有效率仅为30%～50%,且激素耐药的重度急性GVHD患者预后极差.间充质干细胞(MSC)可以调节体内外的免疫反应,因此MSC可用于治疗异基因造血干细胞移植后急性GVHD.本研究旨在观察骨髓MSC治疗激素耐药的重度急性GVHD的疗效.     

间充质干细胞在移植治疗中的研究进展

间充质干细胞(MSC)是骨髓微环境中一种重要的、具有多向分化潜能的非造血干细胞.体外研究表明,MSC在类似Dexter型的基质培养体系中,具有支持长期培养启动细胞的功能,体内MSC的共输注可促进造血干细胞的植入,加速移植受者的造血重建.同种异体MSC的共输注可抑制同种异体免疫反应,延长移植物的存活时间,降低移植物抗宿主反应.所以人类MSC具有广泛的临床应用前景.     

间充质干细胞在移植治疗中的研究进展

间充质干细胞(MSC)是骨髓微环境中一种重要的、具有多向分化潜能的非造血干细胞.体外研究表明,MSC在类似Dexter型的基质培养体系中,具有支持长期培养启动细胞的功能,体内MSC的共输注可促进造血干细胞的植入,加速移植受者的造血重建.同种异体MSC的共输注可抑制同种异体免疫反应,延长移植物的存活时间,降低移植物抗宿主反应.所以人类MSC具有广泛的临床应用前景.     

三种方法冻存间充质干细胞存活率的比较

近年来,掀起干细胞研究和应用的热潮,尤其是MSC已经广泛应用于临床各种疾病的治疗,因而,MSC的冷冻保存及其复苏后的存活对干细胞的临床应用尤为重要.本文对三种冻存方法进行了对比,以寻求MSC较佳的冻存方法.     

临床细胞加工与细胞治疗

随着干细胞研究从实验室走向临床,临床细胞加工技术逐步成为热点.起源于造血干细胞移植的细胞加工技术,在发展中对条件与技术的要求越来越严格和规范.该文深入探讨了临床细胞治疗中的常见种类和方法,如应用免疫磁珠筛选外周血CD34 的造血干细胞;通过体外筛选、共培养和纯化技术改良淋巴细胞,防范移植物抗宿主或进行过继免疫治疗血液系统肿瘤或实体瘤;脐血造血干细胞移植的方法和优缺点;骨髓间充质干细胞的富集和体外扩增等加工技术及其诸多临床应用;树突状细胞体外激活后移植治疗肿瘤、胰岛细胞移植治疗Ⅰ型糖尿病、角膜缘干细胞移植修复角膜、神经干细胞移植治疗脑外伤和帕金森等疾病的技术方法和现状.还明确了目前临床细胞治疗的潜力和价值,强调了规范治疗的必要性.     

造血干细胞移植术后生物学行为的影响

一、造血干细胞简介造血干细胞移植技术飞速进展,已成为当今治愈多种良、恶性血液病与遗传性疾病的重要手段［1］,受益病种还在不断扩大。但是,这种治疗方式对于患者来说仍然具有高风险及高死亡率［2］。国内外相关研究已经证实,在其他癌症人群中,心理因素、免疫功能和临床结果之间有着显著的相关性,但对于接受造血干细胞移植的血液病患者尚无相关的研究报道,这类特殊人群的生物学行为是否与疾病有一定的相关性,能否在预防感染、减轻移植物抗宿主病反应、消除恶性细胞及免疫恢复调节过程中能否起到关键作用,从而降低患者的病死率尚不清楚。国外研究表明,造血干细胞移植后的生物学干预可能会影响移植后的免疫功能状态,造血干细胞移植后的恢复早期可能是进行生物学行为干预的一个窗口期,可能会影响造血干细胞移植患者的生存状态及生活质量［3］。造血干细胞移植治疗过程中实施的一系列方法都是科学及严谨的,但这种治疗方法依然存在着很高的复发率和死亡率。心理神经免疫学研究已广泛应用于其他癌症人群,但对于接受造血干细胞移植的患者却鲜有报道,及时的免疫调节可能在降低发病率、减少并发症及预防复发方面有重要作用。     

间充质干细胞在骨性关节炎治疗中的应用

骨关节炎(OA)是一种以关节软骨变性、破坏及骨质增生为特征的慢性关节退行性疾病。作为全球公共卫生的一种代表性疾病,其患病率随着人口老龄化而迅速增长。近年来,随着间充质干细胞(MSC)作为可行性治疗的发现,其在骨性关节炎治疗中修复破坏软骨的潜能正在研究中。但仍需要进一步前瞻性研究来证明其在临床试验中的功效。本文复习了MSC功能特性和分泌滋养功能,以及MSC衍生的胞外囊泡的作用,并对前期临床试验中的治疗方法和结果进行综述。     

Editorial Commentary: Stem Cell Therapy for the Knee: Heterogeneity in Cell Sources,Delivery Methods,and Concomitant Surgery Needs to Be Considered

Mesenchymal stem cells (MSCs) have been investigated for the treatment of knee osteoarthritis because of their unique properties, including self-renewal, multi-linear cellular differentiation, and immunomodulatory capacity. However, the efficacy of MSCs for positive clinical outcomes in the treatment of knee osteoarthritis remains controversial. Because clinical studies in general have high variability, the heterogeneity in the sources of the stem cells used, efficacy of delivery methods, and concomitant surgery should be carefully considered to interpret the benefits of MSC therapy for knee osteoarthritis.     

Innovation in the Treatment of Uremia: Proceedings from the Cleveland Clinic Workshop: Cellular Therapy of Kidney Diseases

The understanding of cellular sources of kidney regeneration has rapidly evolved in the last decade. It is now believed that regeneration occurs predominantly from cells that reside within the injured kidney, with minimal contribution from extra‐renal cells. We now know that improved kidney regeneration seen following exogenous administration of stem cells occur predominantly by noncellular paracrine mechanisms. Of all extra‐renal stem cells, mesenchymal stem cells (MSC) are the most promising stem cell type for treating kidney diseases. There is an ongoing clinical trial evaluating safety and efficacy of MSC in treating acute kidney injury (AKI). Results of this trial are expected to bring use of MSC closer to the clinical realm. An improved understanding of the small molecules that facilitate kidney regeneration and are secreted by MSC will likely result in the development of new therapies for treating AKI. Identification of adult stem cell markers will result in improved understanding of pathophysiology of kidney diseases and could lead to the development of new cellular therapies. Directed differentiation of stem cells into desired cell types such as erythropoietin producing cells will allow selective replacement of lost kidney function. Cell‐based therapies for patients with chronic kidney disease are presently in proof‐of‐principle stage and are expected to evolve in the coming years with improved understanding of stem cell biology. Technological advancement in cellular therapy is expected to provide improved therapeutic options for patients with kidney diseases in the near future.     

间充质干细胞防治慢性移植物抗宿主病：进展与挑战

慢性移植物抗宿主病(cGVHD)是异基因造血干细胞移植后的主要并发症,也是导致非复发死亡的主要原因,因其病理生理过程复杂,常规糖皮质激素联合免疫抑制药的防治有效率不足50%。对于糖皮质激素抵抗的cGVHD患者需启动二线治疗,然而目前的二线治疗方法尚未形成共识,且治疗效果不佳。间充质干细胞(MSC)是最常见的成体干细胞之一,因其具有多维度、多靶点的免疫调控功能,已被广泛应用于cGVHD的预防及治疗,且大量研究证实了MSC治疗cGVHD的安全性和有效性,有望成为cGVHD防治的新策略。本文主要围绕MSC防治cGVHD的研究进展、作用机制及存在的问题等方面进行综述,以期为今后优化MSC治疗方案、提高cGVHD防治效果提供新思路。     

Potential of mesenchymal stem cells as immune therapy in solid-organ transplantation

Over the last decade, there has been a rising interest in the use of mesenchymal stem cells (MSCs) for clinical applications. This interest stems from the beneficial properties of MSCs, which include multi-lineage differentiation and immunosuppressive ability, suggesting there is a role for MSC therapy for tissue regeneration and in immunologic disease. Despite recent clinical trials investigating the use of MSCs in treating immune-mediated disease, their applicability in solid-organ transplantation is still unknown. In this review, we identified topics that are important when considering MSC therapy in clinical organ transplantation. Whereas, from other clinical studies, it would appear that administration of MSCs is safe, issues like dosing, timing, route of administration, and in particular the use of autologous or donor-derived MSCs may be of crucial importance for the functional outcome of MSCs treatment in organ transplantation. We discuss these topics and assess the feasibility of MSCs therapy in organ transplantation.     

Prepare cells to repair the heart: mesenchymal stem cells for the treatment of heart failure

Heart failure is one of the most important cardiovascular diseases, with high mortality, and invasive treatment such as mechanical circulatory support and cardiac transplantation is sometimes required for severe heart failure. Therefore, the development of less invasive and more effective therapeutic strategies is desired. Cell therapy is attracting growing interest as a new approach for the treatment of heart failure. As a cell source, various kinds of stem/progenitor cells such as bone marrow cells, endothelial progenitor cells, mesenchymal stem cells (MSC) and cardiac stem cells have been investigated for their efficacy and safety. Especially, bone marrow-derived MSC possess multipotency and can be easily expanded in culture, and are thus an attractive therapeutic tool for heart failure. Recent studies have revealed the underlying mechanisms of MSC in cardiac repair: MSC not only differentiate into specific cell types such as cardiomyocytes and vascular endothelial cells, but also secrete a variety of paracrine angiogenic and cytoprotective factors. It has also been suggested that endogenous MSC as well as exogenously transplanted MSC migrate and participate in cardiac repair. Based on these findings, several clinical trials have just been started to evaluate the safety and efficacy of MSC for the treatment of heart failure.     

Mesenchymal stem cells: immunobiology and therapeutic potential in kidney disease

SUMMARY: Mesenchymal stem cells (MSC) are non‐haematopoietic cells that are prevalent in the adult bone marrow but can also be isolated from a variety of other postnatal tissues. MSC are non‐immunogenic and are immunosuppressive, with the ability to inhibit maturation of dendritic cells and suppress the function of naïve and memory T cells, B cells and NK cells. In addition to their immunomodulatory properties, MSC are capable of differentiating into various tissues of mesenchymal and non‐mesenchymal origin and migrating to sites of tissue injury and inflammation to participate in tissue repair. A number of studies in animal models of cardiac injury, stroke and ischaemic renal injury have demonstrated the clinical potential of MSC in tissue regeneration and repair. MSC are currently being evaluated in various preclinical and clinical studies in humans and offer significant potential as a novel cellular therapy for tissue regeneration and immunological conditions. The present review focuses on the unique immunomodulatory and regenerative properties of MSC and their potential role in the treatment of kidney disease.     

Sensitive balance of suppressing and activating effects of mesenchymal stem cells on T-cell proliferation

The human leukocyte antigen-independent immune-modulatory potential of human mesenchymal stem cells (hMSC) makes them a promising candidate for clinical cell therapy. A better understanding of their "immune-privileged" status is therefore of high priority. Here we used Ki-67-antigen staining to estimate T-cell alloreactivity in mixed lymphocyte cultures in the presence of hMSC as second or third party. We found that the allostimulatory activity of mesenchymal stem cells (MSC) leading to an increased T-cell proliferation and interleukin-2 secretion is measurable only at low MSC/effector ratios (< or =0.1:1). Moreover, this stimulating effect could be efficiently suppressed by MSC-conditioned medium. This suggests that the "immune-privileged" status of MSC exists only when MSC-mediated downregulation of immune cell activation can overrule their own allostimulatory potential. Thus the "immune-privileged" state of MSC represents a sensitive balance of suppressing and activating effects, which should be considered in a clinical setting with limited cell amounts.     

Immunomodulation by mesenchymal stem cells: a potential therapeutic strategy for type 1 diabetes

Mesenchymal stem cells (MSCs) are pluripotent stromal cells that have the potential to give rise to cells of diverse lineages. Interestingly, MSCs can be found in virtually all postnatal tissues. The main criteria currently used to characterize and identify these cells are the capacity for self-renewal and differentiation into tissues of mesodermal origin, combined with a lack in expression of certain hematopoietic molecules. Because of their developmental plasticity, the notion of MSC-based therapeutic intervention has become an emerging strategy for the replacement of injured tissues. MSCs have also been noted to possess the ability to impart profound immunomodulatory effects in vivo. Indeed, some of the initial observations regarding MSC protection from tissue injury once thought mediated by tissue regeneration may, in reality, result from immunomodulation. Whereas the exact mechanisms underlying the immunomodulatory functions of MSC remain largely unknown, these cells have been exploited in a variety of clinical trials aimed at reducing the burden of immune-mediated disease. This article focuses on recent advances that have broadened our understanding of the immunomodulatory properties of MSC and provides insight as to their potential for clinical use as a cell-based therapy for immune-mediated disorders and, in particular, type 1 diabetes.     

Mesenchymal stem cell–based therapy for nonhealing wounds: today and tomorrow

Although advancements have been made with traditional therapies, the treatment of chronic nonhealing wounds still remains a tough challenge. In the past two decades, mesenchymal stem cell (MSC)–based therapy has emerged as a promising therapeutic strategy for nonhealing wounds because of their characteristics including self‐renewal and a multidirectional differentiation ability and their easy collection and weak immunogenicity. There is a growing body of basic scientific studies that shed light on the functional mechanism of MSCs in modulating nonhealing wounds. Furthermore, critical advances have been achieved using MSC‐based therapy in preclinical animal models as well as in clinics trials. In this present review, we summarize the mechanisms of MSCs and highlight the important preclinical and clinical trials of MSC therapy for nonhealing wounds. In particular, the combination of MSCs transplantation and tissue‐engineered skin is addressed as a new strategy to optimize the delivery efficiency and therapeutic potential. Additionally, the current drawbacks of MSC therapy and the potential to further optimize the use of MSCs are implied.