间充质干细胞与肿瘤形成的研究进展

间充质干细胞(Mesenchymal stem cells,MSCs)具有独特的免疫调节作用、自我更新和跨胚层多向分化的潜能,存在于许多组织中并活跃地向组织损伤部位迁移,参与伤口修复。在对肿瘤的信号发生反应后,MSCs不断被招募并成为肿瘤微环境的成分。肿瘤相关MSCs(Tumor-associated MSCs, TA-MSCs)在肿瘤发生、促进、进展和转移中有重要作用。本文对MSCs在调节肿瘤细胞的存活、增殖、迁移、药物抵抗中如何发挥作用,以及MSCs对肿瘤微环境免疫状态的影响作一综述。我们强调了MSCs和其他肿瘤基质细胞之间的复杂关系,特别是炎症细胞可以改变肿瘤微环境的免疫状态,以期通过对TA-MSCs进一步的研究来取得对不同肿瘤类型和肿瘤进展不同阶段中肿瘤相关MSCs功能的更好的理解,并优化MSCs来得到更有效和安全的MSCs为基础的肿瘤治疗。MSCs已被有效用于治疗慢性炎性疾病和慢性损伤,因此,其机制方面的研究还有利于在其他疾病中合理利用MSCs从而达到疾病治疗的目的。     

模拟干细胞生长微环境以促进间充质干细胞的扩增

间充质干细胞（mesenchyrmalstemcells,MSCs）是当前在多种组织再生和细胞治疗研究中被最广泛采用的一类干细胞。但如何诱导MSCs的体外高效扩增并维持其干性特征（stemness）,从而为临床应用提供充足、优质的细胞源,是当前基础研究和临床治疗中遇到的瓶颈问题。日益增多的研究表明,机体内干细胞的自我更新与分化受其所处体内微环境的紧密调控。因此,精确模拟干细胞在体内生长的微环境已成为提高干细胞体外扩增效率的重要策略。该文就近期研究中如何模拟干细胞生长微环境诱导MSCs体外扩增并维持干细胞特性的研究做一综述,为今后MSCs的高效扩增和推进临床运用与转化提供思路。     

间充质干细胞与免疫的相互作用:从基础研究到临床应用

间充质干细胞(mesenchymal stem cells,MSCs)是一种广泛存在于组织基质微环境中的多能干细胞,可以从多种组织中分离获得,如骨髓、脂肪、脐带等。MSCs具有向脂肪细胞、成骨细胞、软骨细胞分化的多向分化潜能和强而有力的免疫调节作用,在多种疾病的治疗中具有广阔的应用前景。无论是内源性MSCs还是外源输注的MSCs,均具有向损伤组织迁移的特性,参与调节组织修复过程,其中损伤组织中的炎症与MSCs的相互作用在决定MSCs的修复特性中发挥不可或缺的作用。不仅炎症因子刺激MSCs的免疫抑制作用,而且,炎症因子的浓度和种类可以调节MSCs发挥免疫抑制或增强作用,决定MSCs免疫调节作用的可塑性。重点讨论MSCs与免疫的交互调控在疾病致病及治疗中的作用及意义。     

间充质干细胞在疾病治疗中的应用潜力

间充质干细胞（mesenchymal stem cell,MSCs）是衍生自中胚层的多能细胞,可产生多种间充质谱系,包括成骨细胞、脂肪细胞、成软骨细胞和肌细胞。MSCs还具有分泌多种细胞因子的能力,可促进血管生成、上皮再生等,在再生医学领域具有巨大的潜力。研究证实,MSCs可通过分化为多种细胞类型促进组织再生,加速伤口愈合;通过分泌细胞因子改善组织纤维化;还可通过携带载体药物诱导肿瘤细胞的凋亡,抑制肿瘤的发展。然而MSCs的成纤维化潜能和促进肿瘤生长的能力降低了MSCs应用于临床治疗的安全性。总结了MSCs在肿瘤、慢性难愈合伤口、纤维化等疾病发展过程中的作用,并进一步讨论了MSCs在临床相关疾病治疗中的潜在应用价值及挑战,以期为间充质干细胞的临床应用提供参考。     

间充质干细胞影响肿瘤细胞增殖及其分子机理

间充质干细胞MSCs(mesenchymal stem cells)与肿瘤细胞间的相互作用是近年来肿瘤领域的研究热点之一.MSCs是一种多能干细胞,具有分化为成骨细胞、软骨细胞、脂肪细胞、纤维母细胞或肌肉细胞等多种间充质细胞的能力.MSCs在肿瘤细胞中表现出的归巢和转移能力为其成为潜在的抗肿瘤工具奠定了基础,MSCs转移到肿瘤细胞后参与重塑肿瘤微环境,并对其增殖、侵袭和转移等生物学行为产生重要影响.MSCs重塑肿瘤微环境后对肿瘤细胞的增殖究竟是促进还是抑制,相关文献报道有很大的争议.基于相关研究近况,主要综述骨髓间充质干细胞BMSCs(bone marrow derived mesenchymal stem cells)参与重塑肿瘤微环境对肿瘤细胞增殖的影响,并就已知的分子机理做一简要介绍.     

间充质干细胞来源外泌体在膝骨关节炎微环境中的作用

骨关节炎是一种涉及所有关节成分（包括关节软骨、软骨下骨、滑膜、韧带、关节囊和关节周围肌肉）的关节退行性疾病，会导致严重的残疾，其中最常见的是膝骨关节炎（knee osteoarthritis，KOA）。外泌体是一种由不同细胞分泌的直径为40~100 nm的胞外囊泡，可以传递DNA、微小RNA、mRNA、蛋白质等多种物质，并通过多种方式进行细胞间的信息传递和功能调节。间充质干细胞（mesenchymal stem cells，MSCs）可以从骨髓、脂肪、滑膜及外周血等组织分离，是一类具有多向分化潜能的祖细胞，以干细胞为基础的疗法可以修复软骨损伤，对抗KOA的发展，间充质干细胞能够分泌多种营养因子来调节受损的微环境，其中间充质干细胞来源的外泌体被认为在KOA炎症反应及软骨细胞代谢中发挥着重要的作用，其能够调节膝骨关节微环境中B细胞、T细胞、滑膜细胞、软骨细胞代谢及其细胞外基质的分解与合成平衡，维持软骨稳态。近期有多项研究表明，不同组织来源的间充质干细胞外泌体对骨关节炎均有明确的治疗作用，本文就MSCs来源的外泌体治疗KOA的具体机制进行综述，以期对干细胞治疗KOA提供理论依据。     

间充质干细胞促肿瘤细胞迁移侵袭研究进展

肿瘤转移是大多数癌症患者的重要致死原因,一旦发生转移,肿瘤患者生存率与生存质量明显下降.肿瘤细胞迁移/侵袭能力是转移的关键,其发生机制受到多种因素的影响.大量研究证明,间充质干细胞(mesenchymal stem cells,MSCs)与肿瘤细胞迁移/侵袭之间有着密切关系.本文就MSCs对肿瘤细胞迁移/侵袭能力的影响...     

间充质干细胞在炎症性疾病治疗中的基础研究和临床应用

间充质干细胞/基质细胞(mesenchymal stem/stromal cells, MSCs),由于其独特的免疫调节能力而备受关注。在治疗克罗恩病、移植物抗宿主病、系统性红斑狼疮以及器官纤维化等炎症性疾病的临床研究和应用中, MSCs均被报道可以抑制炎症,缓解疾病进展,展现出了良好的药用前景。MSCs调控炎症微环境、改善疾病的方式有很多,总体而言,在强烈炎症因子的刺激下, MSCs可以重塑组织微环境,使之向有利于再生和免疫正常化的方向转变。机制上,在炎症因子的刺激下,MSCs通过产生免疫抑制分子、生长因子、趋化因子、补体以及代谢产物等,调控多种免疫细胞的迁移、增殖和活化等生物过程以达到调控炎症微环境的目的。更新的报道甚至提出凋亡的MSCs也能发挥免疫抑制的功能。此外, MSCs的免疫调节能力受炎症因子调控,不是与生俱来又一成不变的,因此,依据微环境中炎症因子的种类、水平, MSCs的免疫调节功能也会发生变化。该文主要总结了近年来人们对MSCs免疫调节机制、MSCs与炎症微环境相互作用的理解以及应用MSCs治疗炎症性疾病的临床现状。     

间充质干细胞来源细胞外囊泡对肺部疾病作用研究进展

细胞外囊泡(extracellular vesicles, EVs)是细胞自然分泌的脂质囊泡结构,在生理和病理过程中发挥信息交流作用。间充质干细胞(mesenchymal stromal cell, MSCs)是一种来源广泛的多能基质干细胞,其强大的再生潜能及免疫调节能力在肺部疾病的修复和治疗中显示出广阔前景。间充质干细胞来源细胞外囊泡(mesenchymal stromal cell extracellular vesicles, MSCs-EV)具有类似MSCs的功能特性,其携带的多种活性因子在肺部组织、肺微环境及肺部疾病中展现出良好治疗效果。主要总结了MSCs及MSCs-EV生物特性,深入讨论了MSCs-EV在肺部疾病中的作用机制及临床应用价值。     

间充质干细胞与肿瘤转移

间充质干细胞是一类能够自我更新、具有多向分化潜能的成体干细胞。近年来,有证据认为间充质干细胞是肿瘤组织中基质细胞的祖先,因此间充质干细胞微环境与肿瘤转移的关系逐渐成为研究热点,但间充质干细胞对肿瘤转移是促进还是抑制,目前的研究并不一致。我们简要综述了间充质干细胞参与肿瘤转移的研究进展。     

Immunosuppressive effect of bone marrow-derived mesenchymal stem cells in inflammatory microenvironment favours the growth of B16 melanoma cells

Mesenchymal stem cells (MSCs) are studied for their potential clinical use in regenerative medicine, tissue engineering and tumour therapy. However, the therapeutic application of MSCs in tumour therapy still remains limited unless the immunosuppressive role of MSCs for tumour growth in vivo is better understood. In this study, we investigated the mechanism of MSCs favouring tumour escape from immunologic surveillance in inflammatory microenvironment. We first compared the promotive capacity of bone marrow-derived MSCs on B16 melanoma cells growth in vivo, pre-incubated or not with the inflammatory cytokines interferon (IFN)-γ and tumour necrosis factor (TNF)-α. We showed that the development of B16 melanoma cells is faster when co-injected with MSCs pre-incubated with IFN-γ and TNF-α compared with control groups. Moreover, tumour incidence increases obviously in allogeneic recipients when B16 melanoma cells were co-injected with MSCs pre-incubated with IFN-γ and TNF-α. We then demonstrated that the immunosuppressive function of MSCs was elicited by IFN-γ and TNF-α. These cytokine combinations provoke the expression of inducible nitric oxide synthase (iNOS) by MSCs. The impulsive effect of MSCs treated with inflammatory cytokines on B16 melanoma cells in vivo can be reversed by inhibitor or short interfering RNA of iNOS. Our results suggest that the MSCs in tumour inflammatory microenvironment may be elicited of immunosuppressive function, which will help tumour to escape from the immunity surveillance.     

Role of mesenchymal stromal cell-derived extracellular vesicles in tumour microenvironment

Stromal cells, deriving from mesenchymal stromal cells (MSCs), are crucial component of tumour microenvironment and represent key regulators of tumour processes. MSCs can be recruited to the tumour environment and interact with many cellular elements, thus influencing tumour biology. Cell-to-cell communication is in part mediated by the release of extracellular vesicle (EVs). EVs can induce significant molecular changes in recipient cells, delivering bioactive molecules. In this review, we describe the MSC-derived EVs content and discuss their role in different processes related to cancer biology. Furthermore, we summarize chemical or biological EVs modifications aiming to develop more efficient antitumor therapies.     

Rat bone marrow mesenchymal stem cells undergo malignant transformation via indirect co‐cultured with tumour cells

Mesenchymal stem cells (MSCs) have potential applications in regenerative medicine and tissue engineering as well as being potential carriers for tumour therapy. However, the safety of using MSCs in tumours is unknown. Herein, we analyse malignant transformation of MSCs in the tumour microenvironment. Rat bone marrow MSCs were cultured with malignant rat glioma C6 cells without direct cell–cell contact. After 7 days, the cells were assessed for transformation using flow cytometry, real‐time quantitative PCR, immunofluorescence and chromosomal analysis. In addition, wild‐type (WT) p53, mutant p53 and mdm2 was determined using Western blotting. Almost all MSCs became phenotypically malignant cells, with significantly decreased WT p53 expression and increased expression of mutant p53 and mdm2, along with an aneuploid karyotype. To evaluate tumorigenesis in vivo, the MSCs indirect co‐cultured with C6 cells for 7 days were transplanted subcutaneously into immuno‐deficient mice. The cells developed into a large tumour at the injection site within 8 weeks, with systemic symptoms including cachexia and scoliosis. Pathological and cytological analysis revealed poorly differentiated pleomorphic cells with a dense vascular network and aggressive invasion into the adjacent muscle. These data demonstrate that MSCs became malignant cancer cells when exposed to the tumour microenvironment and suggest that factors released from the cancer cells have a critical role in the malignant transformation of MSCs. Copyright © 2012 John Wiley & Sons, Ltd.     

The MSC: an injury drugstore

Now that mesenchymal stem cells (MSCs) have been shown to be perivascular in?vivo, the existing traditional view that focuses on the multipotent differentiation capacity of these cells should be expanded to include their equally interesting role as cellular modulators that brings them into a broader therapeutic scenario. We discuss existing evidence that leads us to propose that during local injury, MSCs are released from their perivascular location, become activated, and establish a regenerative microenvironment by secreting bioactive molecules and regulating the local immune response. These trophic and immunomodulatory activities suggest that MSCs may serve as site-regulated "drugstores" in?vivo.     

Tumour‐associated fibroblasts and mesenchymal stem cells: more similarities than differences

Tumour‐associated fibroblasts (TAFs) are part of the tumour stroma, providing functional and structural support for tumour progression and development. The origin and biology of TAFs are poorly understood, but within the tumour environment, TAFs become activated and secrete different paracrine and autocrine factors involved in tumorigenesis. It has been shown that bone marrow mesenchymal stem cells (MSCs) can be recruited into the tumours, where they proliferate and acquire a TAF‐like phenotype. We attempted to determine to what extent TAFs characteristics in vitro juxtapose to MSCs’ definition, and we showed that TAFs and MSCs share immunophenotypic similarities, including the presence of certain cell surface molecules [human leukocyte antigen‐DR subregion (HLA‐DR), CD29, CD44, CD73, CD90, CD106 and CD117]; the expression of cytoskeleton and extracellular matrix proteins, such as vimentin, α‐smooth muscle actin, nestin and trilineage differentiation potential (to adipocytes, chondrocytes and osteoblasts). When compared to MSCs, production of cytokines, chemokines and growth factors showed a significant increase in TAFs for vascular endothelial growth factor, transforming growth factor‐β1, interleukins (IL‐4, IL‐10) and tumour necrosis factor α. Proliferation rate was highly increased in TAFs and fibroblast cell lines used in our study, compared to MSCs, whereas ultrastructural details differentiated the two cell types by the presence of cytoplasmic elongations, lamellar content lysosomes and intermediate filaments. Our results provide supportive evidence to the fact that TAFs derive from MSCs and could be a subset of ‘specialized’ MSCs.     

Immunosuppressive cells and tumour microenvironment: focus on mesenchymal stem cells and myeloid derived suppressor cells

Tumours have been compared to unhealed wounds that produce large amounts of inflammatory mediators, including cytokines, chemokines, and growth factors. These molecules participate in the formation of a rich and heterogeneous microenvironment by attracting non malignant cells that promote tumour progression and dissemination. Tumour infiltrating cells include macrophages, myeloid-derived suppressor cells (MDSCs), mesenchymal stromal cells (MSCs) and TIE2-expressing monocytes. Most of them are bone marrow-derived, although MSC are present in virtually every tissue. This review focuses on MDSCs and MSCs, both of which can exert pro-tumorigenic effects through negative regulation of immune responses. MDSCs represent a heterogeneous population of cells of myeloid origin that are expanded and activated in response to growth factors and cytokines released by tumours. Once MDSCs are activated, they accumulate in lymphoid organs and tumours where they exert T cell immunosuppression. Like MDSCs, MSCs can be mobilized from the bone marrow into the bloodstream and home in the tumour stroma, where they either help or hinder tumour growth. Here, we will discuss the origin, the functions and the mechanisms of action of MSCs and MDSCs, as well as the strategies to target these cells for the therapeutic benefit of cancer patients.     

A20 plays a critical role in the immunoregulatory function of mesenchymal stem cells

Mesenchymal stem cells (MSCs) possess an immunoregulatory capacity and are a therapeutic target for many inflammation‐related diseases. However, the detailed mechanisms of MSC‐mediated immunosuppression remain unclear. In this study, we provide new information to partly explain the molecular mechanisms of immunoregulation by MSCs. Specifically, we found that A20 expression was induced in MSCs by inflammatory cytokines. Knockdown of A20 in MSCs resulted in increased proliferation and reduced adipogenesis, and partly reversed the suppressive effect of MSCs on T cell proliferation in vitro and inhibited tumour growth in vivo. Mechanistic studies indicated that knockdown of A20 in MSCs inhibited activation of the p38 mitogen‐activated protein kinase (MAPK) pathway, which potently promoted the production of tumour necrosis factor (TNF)‐α and inhibited the production of interleukin (IL)‐10. Collectively, these data reveal a crucial role of A20 in regulating the immunomodulatory activities of MSCs by controlling the expression of TNF‐α and IL‐10 in an inflammatory environment. These findings provide novel insights into the pathogenesis of various inflammatory‐associated diseases, and are a new reference for the future development of treatments for such afflictions.     

Mesenchymal stem cells promote cell invasion and migration and autophagy‐induced epithelial‐mesenchymal transition in A549 lung adenocarcinoma cells

Mesenchymal stem cells (MSCs) are recruited into the tumour microenvironment and promote tumour growth and metastasis. Tumour microenvironment‐induced autophagy is considered to suppress primary tumour formation by impairing migration and invasion. Whether these recruited MSCs regulate tumour autophagy and whether autophagy affects tumour growth are controversial. Our data showed that MSCs promote autophagy activation, reactive oxygen species production, and epithelial‐mesenchymal transition (EMT) as well as increased migration and invasion in A549 cells. Decreased expression of E‐cadherin and increased expression of vimentin and Snail were observed in A549 cells cocultured with MSCs. Conversely, MSC coculture‐mediated autophagy positively promoted tumour EMT. Autophagy inhibition suppressed MSC coculture‐mediated EMT and reduced A549 cell migration and invasion slightly. Furthermore, the migratory and invasive abilities of A549 cells were additional increased when autophagy was further enhanced by rapamycin treatment. Taken together, this work suggests that microenvironments containing MSCs can promote autophagy activation for enhancing EMT; MSCs also increase the migratory and invasive abilities of A549 lung adenocarcinoma cells. Mesenchymal stem cell‐containing microenvironments and MSC‐induced autophagy signalling may be potential targets for blocking lung cancer cell migration and invasion.