TSP-1-Mediated Induction of T Regulatory Cell by Adipose-Derived Mesenchymal Stem Cells: A Mechanism of Immunosuppression.
TSP-1-Mediated Induction of T Regulatory Cell by Adipose-Derived Mesenchymal Stem Cells: A Mechanism of Immunosuppression.
复制标题
TSP-1 介导的脂肪源性间充质干细胞诱导 T 调节细胞：免疫抑制机制。
DOI：
10.1007/s10620-017-4645-4
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发表时间：
2017
影响因子：
3.1
通讯作者：
Dave,Maneesh
中科院分区：
文献类型：
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作者：
Dave,Maneesh
成体间充质干细胞（MSC），包括脂肪源性干细胞（ASC），在体外和结肠炎小鼠模型中具有强效免疫抑制活性[1]。多项正在进行的临床试验研究了ASC治疗炎症性肠病（IBD）和其他免疫介导疾病的患者[2，3]。ASC更常用于基于细胞的治疗，因为它们普遍存在，易于获取，并且从脂肪组织中获得高产率。最近的一项III期多中心随机安慰剂对照试验将同种异体脂肪干细胞直接注射到克罗恩病肛周瘘[4]中，报告了临床和放射学愈合。如果MSC疗法已经在临床上有效，为什么要在小鼠中进行研究？不幸的是，来自使用全身施用的MSC治疗IBD中的粘膜病变的临床试验的数据显示出良好的安全性，但没有明确的疗效信号[2]。尽管一些研究表明调节性T细胞（Treg）诱导有助于MSC的治疗益处，但其原因尚未得到充分研究，需要在临床前模型中进行额外的机制研究，以帮助理解MSC给药的治疗益处。Takeyama及其同事在本期《消化系统疾病与科学》中的研究很重要，因为它报告了表达血小板反应蛋白-1（TSP-1）的ASC激活转化生长因子β（TGF-b）是Treg细胞诱导的机制，并在小鼠葡聚糖硫酸钠（DSS）结肠炎模型中产生治疗益处[5]。作者证明，腹腔内（ip）给予ASC可改善DSS诱导的急性结肠炎，并增加结肠固有层和肠系膜淋巴结（MLN）中的TcR数量，如流式细胞术所评估。T细胞的增加并不伴随着CD 103+树突状细胞的增加，这表明ASC因子的作用有助于CD 103+树突状细胞诱导T细胞。此外，在共培养试验中，作者确定ASC不分泌TGF-β，而是通过TSP-1激活潜伏的TGF-β。使用siRNA敲低ASC中的TSP-1（TSP-1 KO），他们表明TSP-1 KO ASC在体内不诱导THP，并且与模拟处理（非靶向siRNA对照）和未处理的ASC相比，未能改善结肠炎。使用绿色荧光蛋白标记的ASC，作者表明ASC不迁移到结肠发挥其作用，而是在脾脏和MLN中发现。尽管他们的结果与其他研究一致，这些研究表明，在ip注射后MSC有限地归巢到结肠，但Sala及其同事的一项优雅的研究报告称，MSC（包括ASC）在注射部位形成腹膜聚集体，并且不归巢到脾脏或MLN [6]。这种不一致性可能是由于这些研究中使用的ASC制剂与脾脏和MLN上腹膜聚集体沉积之间趋化因子受体CCR 7和CCR 9的差异表达。未来的研究需要使用动态成像技术，如双光子显微镜，以澄清归巢和MSC与宿主细胞的相互作用。
Adult mesenchymal stem cells (MSC), including adiposederived stem cells (ASC), have potent immunosuppressive activity in vitro and in mouse models of colitis [1]. Multiple ongoing clinical trials have studied ASC in the treatment of patients with inflammatory bowel diseases (IBD) and other immune-mediated diseases [2, 3]. ASCs are more frequently used for cell-based therapy given their ubiquity, ease of acquisition, and the high yield from adipose tissue. A recent phase III multicenter randomized placebo-controlled trial of allogeneic adipose stem cells injected directly into Crohn’s perianal fistulas [4] reported clinical and radiological healing. If MSC therapies are already clinically effective, why study them in mice? Unfortunately, the data from clinical trials using systemically administered MSCs for the treatment of mucosal lesions in IBD have shown good safety but no clear efficacy signal [2]. Although some studies have indicated that T regulatory (Treg) cell induction contributes toward the therapeutic benefits of MSC, the reasons for this are inadequately investigated, requiring additional mechanistic studies conducted in preclinical models to help understand the therapeutic benefits of MSC administration. The study by Takeyama and colleagues in this issue of Digestive Diseases and Sciences is important as it reports that transforming growth factor beta (TGF-b) activation by ASC expressing thrombospondin-1 (TSP-1) is a mechanism for Treg cell induction and consequent therapeutic benefit in a murine dextran sulfate sodium (DSS) colitis model [5]. The authors demonstrate that ASCs administered intraperitoneally (ip) ameliorated DSS-induced acute colitis and increased the number of Tregs in the colonic lamina propria and mesenteric lymph nodes (MLNs) as assessed by flow cytometry. The increase in Tregs was not accompanied by an increase in CD103+ dendritic cells suggesting the role of an ASC factor that helps CD103+ dendritic cells to induce Tregs. Furthermore, in co-culture assays the authors determined that ASCs do not secrete TGF-b but activate latent TGF-b via TSP-1. Using siRNA to knockdown TSP-1 in ASCs (TSP-1KO), they showed that TSP-1 KO ASCs did not induce Tregs in vivo and failed to ameliorate colitis as compared to mocktreated (nontargeted siRNA control) and untreated ASCs. Using green fluorescent protein-labeled ASCs, the authors showed that ASCs do not migrate to the colon to exert their effect but are rather found in the spleen and in the MLNs. Although their results are congruent with other studies that show limited homing of MSCs to the colon after ip injection, an elegant study by Sala and colleagues reported that MSCs (including ASCs) formed peritoneal aggregates at the site of injection and did not home to the spleen or to the MLNs [6]. This discordance could be due to the differential expression of chemokine receptors CCR7 and CCR9 between the ASC preparations used in these studies versus deposition of the peritoneal aggregates on the spleen and the MLNs. Future studies using dynamic imaging techniques such as two-photon microscopy are needed to clarify the homing and interactions of MSCs with host cells.