Human induced pluripotent stem cell-derived mesenchymal stem cells promote healing via TNF- α-stimulated gene-6 in inflammatory bowel disease models
Human induced pluripotent stem cell-derived mesenchymal stem cells promote healing via TNF- α-stimulated gene-6 in inflammatory bowel disease models
复制标题
人诱导多能干细胞来源的间充质干细胞通过 TNF-α 刺激的基因 6 在炎症性肠病模型中促进愈合
DOI：
10.1038/s41419-019-1957-7
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发表时间：
2019
期刊：
影响因子：
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通讯作者：
Shenghong Zhang
中科院分区：
文献类型：
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作者：
Hongsheng Yang;Rui Feng;Qingling Fu;Shu Xu;Xiuxue Hao;Yun Qiu;Ting Feng;Zhirong Zeng;Minhu Chen;Shenghong Zhang
组织来源的间充质干细胞（MSC）的治疗应用受到其有限的扩增能力和供体间差异的阻碍。人诱导多能干细胞（iPSC）衍生的MSC显示出更大的可扩增性，因此提供了用于组织修复疗法的潜力。在此，我们探讨了iPSC-MSCs的再生作用以及iPSC-MSCs通过肿瘤坏死因子-α-刺激基因6（TSG-6）在炎症性肠病（IBD）小鼠模型中促进粘膜愈合的机制。按照临床上符合的方案诱导人iPSC分化成MSC。iPSC-MSC治疗促进了healing.in结肠炎小鼠，伴随着上皮细胞增殖、CD 44阳性细胞和Lgr 5阳性细胞的增加。iPSC-MSC中的TSG-6敲低或PEP-1阻断透明质酸-CD 44相互作用消除了iPSC-MSC的治疗效果，而使用重组TSG-6显示出与iPSC-MSC相似的治疗效果。开发了小鼠或患者来源的类器官培养系统。与iPSC-MSC共培养的类器官显示增加的上皮细胞增殖、CD 44阳性细胞和Lgr 5阳性细胞，其被TSG-6敲低消除。TSG-6诱导的类器官中的促进作用依赖于Akt活化并被抗CD 44抗体或MK 2206消除。总之，iPSC-MSC通过透明质酸-CD 44相互作用以Akt依赖性方式经由TSG-6促进上皮细胞增殖以加速鼠结肠炎模型中的粘膜愈合，证明了用于IBD治疗的患者特异性“现成”形式。
Therapeutic applications of tissue-derived mesenchymal stem cells (MSCs) are hindered by their limited expansion.ability and variation across donors. Human induced pluripotent stem cell (iPSC)-derived MSCs show greater.expandability and therefore offer potential for use in tissue repair therapies. Here we explored the regenerative effects.of iPSC-MSCs and the mechanisms by which iPSC-MSCs promote mucosal healing via tumor necrosis factor-α-.stimulated gene 6 (TSG-6) in mouse models of inflammatory bowel disease (IBD). Human iPSCs were induced to.differentiate into MSCs following a clinically compliant protocol. The iPSC-MSC treatment promoted mucosal healing.in colitic mice, accompanied by increased epithelial cell proliferation, CD44-positive cells, and Lgr5-positive cells. TSG-6.knockdown in iPSC-MSCs or blocking of hyaluronan–CD44 interactions by PEP-1 abrogated the therapeutic effects of.iPSC-MSCs, whereas use of recombinant TSG-6 showed therapeutic effects similar to those of iPSC-MSCs. A mouse or.patient-derived organoid culture system was developed. Organoids co-cultured with iPSC-MSCs showed increased.epithelial cell proliferation, CD44-positive cells, and Lgr5-positive cells, which was abolished by TSG-6 knockdown. TSG-.6-induced promoting effects in organoids were dependent on Akt activation and abrogated by the anti-CD44.antibody or MK2206. In conclusion, iPSC-MSCs promoted epithelial cell proliferation to accelerate mucosal healing in a.murine colitis model via TSG-6 through hyaluronan–CD44 interactions in an Akt-dependent manner, demonstrating a.patient-specific “off-the-shelf” format for IBD treatment.