间充质干细胞的来源及其对肝脏损伤及修复的研究进展

全球终末期肝病、肝衰竭的发病率和死亡率逐年升高,且目前肝移植是唯一疗效确切的治疗选择,但是,肝移植的使用受到肝源供体严重不足,长期存活率低,医疗费用昂贵等缺点使得原位肝移植的应用受限,绝大多数患者无法受益。为了克服肝脏器官短缺,干细胞替代治疗策略逐渐成为另一个肝病治疗的重要选择,干细胞治疗,特别是间充质干细胞（MSC）提供了一个新的肝病治疗选择。MSC是一群贴壁生长的成纤维细胞样细胞,由于MSC能够分化为多种类型的细胞,能够产生多种的细胞因子和生长因子,具有造血支持和免疫调节和抗炎功能,MSC被认为在再生医学领域具有重大的科学和实用价值。另外,由于MSC应用于治疗实验性肝损伤能明显提高动物存活率,明显改善肝功能。此外,一些临床前研究和临床研究也表明MSC对肝损伤性疾病具有显著地疗效。因此MSC在损伤性和退行性肝脏疾病的治疗具有广阔的应用前景。本文综述了MSC在肝损伤疾病治疗应用的进展,并对MSC在肝病治疗中的应用前景进行了展望。     

间充质干细胞与肝缺血再灌注损伤

肝脏手术中普遍发生的缺血再灌注损伤(IRI)可导致肝脏功能损害,目前尚缺乏确切有效的治疗手段。肝脏IRI的机制复杂,炎症反应失衡主导的损伤继发于肝脏理化损害之后,并具有全身性的特点。间充质干细胞(MSC)所具备的免疫调节功能与肝脏IRI中免疫失衡这一重要病理生理过程相契合,凭借其易获取、低免疫源性的特点,故可尝试用于IRI的治疗。目前多项试验初步验证了其有效性,但确切机制有待进一步明确。可见,MSC用于肝脏IRI的治疗拓展了细胞治疗的应用范围,并为肝脏IRI提供了可能的治疗手段。     

间充质干细胞免疫学特性研究进展

间充质干细胞(MSC)是一群中胚层来源的具有自我更新和多向分化潜能的多能干细胞,具有低免疫原性和免疫调节的生物学特性,广泛应用于器官移植、组织创伤修复、细胞治疗等多个领域。随着人们对MSC免疫调节机制研究的不断深入,作为一种疾病治疗新制剂和理想的种子细胞,MSC在异基因造血干细胞移植、自身免疫性疾病治疗和组织工程中的应用备受关注。本文就近年来MSC免疫调节作用和机制的研究进展作一综述。     

Flk1+间充质干细胞减轻四氯化碳导致的肝纤维化的研究

许多慢性肝脏疾病都会发生肝纤维化,但是目前尚缺乏对肝纤维化切实有效的治疗手段。实验发现,Flk1(fetal liver kinase)阳性间充质干细胞(MSC)能够减轻四氯化碳(CCl4)所致小鼠肝纤维化。取雄性BALB／c小鼠骨髓,分离培养Flk1^ MSC,用CCl4制作雌性小鼠肝纤维化模型,在CCl4损伤后立即或1周后经尾静脉注射Flk1^ MSC,2或5周后检测受体小鼠肝脏的纤维化程度和供体细胞的植入。结果发现,CCl4损伤后立即注射Flk1^ MSC,可以使肝脏损伤程度明显减轻,减少胶原沉积,使肝脏羟脯氨酸含量及血清纤维化指标显下降;而损伤1周后注射细胞则无明显变化。免疫荧光、PCR和荧光原位杂交方法证实,在受体肝脏中有供体细胞植入,呈上皮细胞形态,并表达白蛋白,但是数量很少。因此,Flk1^ MSC具有潜在的植入肝组织的能力,并可能启动肝组织的内源性修复,减轻CCl4导致的肝纤维化。     

间充质干细胞的生物学调控及其在骨关节疾病中的应用

间充质干细胞(mesenchymal stem cell,MSC)是一种具有多向分化潜能的干细胞,广泛存在于全身的结缔组织和器官间质中。除具有自我更新和多向分化的能力外,MSC还参与调节免疫应答和炎症反应,这些特性预示了MSC应用于再生医学和治疗炎症性疾病的可行性。本文旨在总结MSC的生物学行为特点,概括机体对MSC在分化、免疫调节等方面的生物学调控,并简要总结了MSC在骨关节疾病中的应用进展。     

间充质干细胞治疗疑难肝病的机遇与挑战

间充质干细胞（MSC）是一群来源于中胚层的多能干细胞,具有多项分化发育潜能。MSC的多潜能性、可扩增性、取材广泛性（骨髓、脐带、脐带血、羊膜、脂肪等组织）等诸多特点为其临床应用奠定了重要基础。在国外,MSC已经获得了临床新药批号,用于移植物抗宿主病（GVHD）的治疗。此外,在心血管疾病、骨及软骨损伤、血液系统疾病、肝脏疾病和自身免疫性疾病等方面,也展示了良好的安全性和初步疗效。尤其是在疑难肝病例如：急性肝衰竭、慢加急性肝衰和失代偿性肝硬化等的临床治疗中也取得了一定效果。疑难肝病的死亡率高,治疗手段有限,需要研发新型、有效的治疗手段来降低死亡率。本文将分析本领域的相关进展,同时分析有关需要解决的问题。     

间充质干细胞治疗糖尿病下肢缺血研究进展

糖尿病下肢缺血是一种严重的糖尿病并发症,可导致下肢感染、溃疡和坏死,严重时甚至需要截肢.传统治疗和外科治疗在临床上亦有诸多局限性,随着以干细胞治疗为主的再生医学兴起,为糖尿病下肢缺血的治疗带来新的可能性.糖尿病下肢缺血的干细胞治疗中最引人瞩目的是间充质干细胞(MSC).MSC是一类具有多向分化潜能且低免疫原性的细胞,通...     

基因修饰的间充质干细胞临床研究进展

基因修饰的间充质干细胞(MSC)可有效地提高移植后细胞存活率,使细胞有效聚集于损伤部位。通过不断优化干细胞和载体选择,有效导入特定基因到MSC内,表达特定蛋白,可用于治疗获得性和遗传性疾病。我们就相关进展及问题做简要阐述,以期为基因修饰的MSC临床应用研究提供借鉴。     

间充质(干)细胞的定义变迁

1966年Friedenstein发现了一群贴壁生长的、成纤维样的,可以体外诱导分化成多种中胚层组织的细胞。1991年Caplan正式命名为间充质干细胞(MSC),成为了全球最常用的描述。随着这群细胞生物学特性研究的进展,MSC到底是不是真正的干细胞引起了争论。目前研究资料表明,MSC的治疗效果主要是通过作为支持细胞分泌生物活性因子,刺激患者体内残留的组织特异性干细胞再生组织,而不是通过其干细胞的特性分化成新的组织。但一些研究者过分强调MSC的干细胞性能,误导患者以为输注的MSC可以再生成新组织。因此,有学者呼吁需将MSC的名称改为间充质细胞或药用信号细胞(medicinal signal cell)。本文将对MSC的定义和起源的发展过程进行梳理,并讨论如何合理的应用MSC的名称。     

我国科学家发现自噬调控MSC免疫机制

<正>近日,中国科学院上海生科院健康科学研究所张雁云小组在一项研究中,首次揭示了自噬调控间充质干细胞免疫功能的作用及机制。相关研究成果已在线发表于《自噬》杂志。间充质干细胞(MSC)已被用于治疗重症肝病、糖尿病和神经损伤等疾病,但自噬对MSC免疫功能的调控作用及其对疾病干预的影响等目前仍不清楚,这些均涉及到MSC治疗的核心机制。     

Pre‐treatments enhance the therapeutic effects of mesenchymal stem cells in liver diseases

Liver diseases caused by viral infection, alcohol abuse and metabolic disorders can progress to end‐stage liver failure, liver cirrhosis and liver cancer, which are a growing cause of death worldwide. Although liver transplantation and hepatocyte transplantation are useful strategies to promote liver regeneration, they are limited by scarce sources of organs and hepatocytes. Mesenchymal stem cells (MSCs) restore liver injury after hepatogenic differentiation and exert immunomodulatory, anti‐inflammatory, antifibrotic, antioxidative stress and antiapoptotic effects on liver cells in vivo. After isolation and culture in vitro, MSCs are faced with nutrient and oxygen deprivation, and external growth factors maintain MSC capacities for further applications. In addition, MSCs are placed in a harsh microenvironment, and anoikis and inflammation after transplantation in vivo significantly decrease their regenerative capacity. Pre‐treatment with chemical agents, hypoxia, an inflammatory microenvironment and gene modification can protect MSCs against injury, and pre‐treated MSCs show improved hepatogenic differentiation, homing capacity, survival and paracrine effects in vitro and in vivo in regard to attenuating liver injury. In this review, we mainly focus on pre‐treatments and the underlying mechanisms for improving the therapeutic effects of MSCs in various liver diseases. Thus, we provide evidence for the development of MSC‐based cell therapy to prevent acute or chronic liver injury. Mesenchymal stem cells have potential as a therapeutic to prolong the survival of patients with end‐stage liver diseases in the near future.     

Current understanding of mesenchymal stem cells in liver diseases

Liver diseases caused by various factors have become a significant threat to public health worldwide. Liver transplantation has been considered as the only effective treatment for end-stage liver diseases; however, it is limited by the shortage of donor organs, postoperative complications, long-term immunosuppression, and high cost of treatment. Thus, it is not available for all patients. Recently, mesenchymal stem cells (MSCs) transplantation has been extensively explored for repairing hepatic injury in various liver diseases. MSCs are multipotent adult progenitor cells originated from the embryonic mesoderm, and can be found in mesenchymal tissues including the bone marrow, umbilical cord blood, adipose tissue, liver, lung, and others. Although the precise mechanisms of MSC transplantation remain mysterious, MSCs have been demonstrated to be able to prevent the progression of liver injury and improve liver function. MSCs can self-renew by dividing, migrating to injury sites and differentiating into multiple cell types including hepatocytes. Additionally, MSCs have immune-modulatory properties and release paracrine soluble factors. Indeed, the safety and effectiveness of MSC therapy for liver diseases have been demonstrated in animals. However, pre-clinical and clinical trials are largely required to confirm its safety and efficacy before large scale clinical application. In this review, we will explore the molecular mechanisms underlying therapeutic effects of MSCs on liver diseases. We also summarize clinical advances in MSC-based therapies.     

Therapeutic potential of bone marrow stem cells for liver diseases

Stem cells of the bone marrow, including hematopoietic stem cells (HSC), mesenchymal stem cells (MSC) and hepatic progenitors were reported to give rise to hepatocytes by both transdifferentiation and cellular fusion. Transdifferentiation was observed without liver damage although significant numbers of stem cell derived hepatocytes were not described. Cellular fusion was demonstrated in the presence of a proliferation stimulus in conjunction with impaired intrinsic liver regeneration capacity. Here, we review potential therapeutic applications of stem cell derived hepatocytes depending on how they emerge. Stem cells turning into hepatocytes by transdifferentiation introduce new functioning liver cells into a diseased organ, which can support intrinsic liver regeneration or bridge the time gap until a definitive treatment is available. When cellular fusion is the mechanism behind stem cell plasticity, however, no new cells emerge in the first place, whereas new genetic material is introduced. The fusion cell thereby acquires a selective advantage over resident hepatocytes allowing for extensive proliferation and liver repopulation. Therefore genetic deficiencies might be the predominant target for cell fusion therapies. We conclude that transdifferentiation and cellular fusion might be powerful tools for the therapy of liver diseases in the future and we propose the introduction of artificial cell fusion as well as stem cell differentiation as therapeutic options.     

Comparative osteogenic transcription profiling of various fetal and adult mesenchymal stem cell sources

Human mesenchymal stem cells (MSC) from adult and fetal tissues are promising candidates for cell therapy but there is a need to identify the optimal source for bone regeneration. We have previously characterized MSC populations in first trimester fetal blood, liver, and bone marrow and we now evaluate their osteogenic differentiation potential in comparison to adult bone marrow MSC. Using quantitative real-time RT-PCR, we demonstrated that 16 osteogenic-specific genes (OC, ON, BSP, OP, Col1, PCE, Met2A, OPG, PHOS1, SORT, ALP, BMP2, CBFA1, OSX, NOG, IGFII) were expressed in both fetal and adult MSC under basal conditions and were up-regulated under osteogenic conditions both in vivo and during an in vitro 21-day time-course. However, under basal conditions, fetal MSC had higher levels of osteogenic gene expression than adult MSC. Upon osteogenic differentiation, fetal MSC produced more calcium in vitro and reached higher levels of osteogenic gene up-regulation in vivo and in vitro. Second, we observed a hierarchy within fetal samples, with fetal bone marrow MSC having greater osteogenic potential than fetal blood MSC, which in turn had greater osteogenic potential than fetal liver MSC. Finally, we found that the level of gene expression under basal conditions was positively correlated with both calcium secretion and gene expression after 21 days in osteogenic conditions. Our findings suggest that stem cell therapy for bone dysplasias such as osteogenesis imperfecta may benefit from preferentially using first trimester fetal blood or bone marrow MSC over fetal liver or adult bone marrow MSC.     

Multilineage differentiation of human MSC after in utero transplantation

Prenatal transplantation of stem cells is an exciting frontier for the treatment of many congenital diseases. The fetus may be an ideal recipient for stem cells, as it is immunologically immature and has rapidly proliferating cellular compartments that may support the engraftment of transplanted cells. Mesenchymal stem cells (MSC), given their ability to differentiate among multiple lineages, could potentially be used to treat diseases such as osteogenesis imperfecta, muscular dystrophy, and a variety of others that can be diagnosed in utero. We have shown, using a human-sheep in utero xenotransplantation model, that human MSC have the ability to engraft, differentiate into many tissue types, and survive for over 1 year in fetal lamb recipients. This observation warrants further studies of the behavior of MSC following systemic or site-directed transplantation.     

Mesenchymal stem cell aging: Mechanisms and influences on skeletal and non-skeletal tissues

The aging population and the incidence of aging-related diseases such as osteoporosis are on the rise. Aging at the tissue and organ levels usually involves tissue stem cells. Human and animal model studies indicate that aging affects two aspects of mesenchymal stem cell (MSC): a decrease in the bone marrow MSC pool and biased differentiation into adipocyte at the cost of osteoblast, which underlie the etiology of osteoporosis. Aging of MSC cells is also detrimental to some non-skeletal tissues, in particular the hematopoietic system, where MSCs serve as a niche component. In addition, aging compromises the therapeutic potentials of MSC cells, including cells isolated from aged individuals or cells cultured for many passages. Here we discuss the recent progress on our understanding of MSC aging, with a focus on the effects of MSC aging on bone remodeling and hematopoiesis and the mechanisms of MSC aging.