Human iPSC-MSC-Derived Xenografts Modulate Immune Responses by Inhibiting the Cleavage of Caspases
Human iPSC-MSC-Derived Xenografts Modulate Immune Responses by Inhibiting the Cleavage of Caspases
复制标题
人 iPSC-MSC 衍生的异种移植物通过抑制 Caspases 的裂解来调节免疫反应
DOI：
10.1002/stem.2638
复制
发表时间：
2017-07-01
期刊：
影响因子：
5.2
通讯作者：
Qi, Zhong-Quan
中科院分区：
文献类型：
--
作者：
Li, Cheng-Lin;Leng, Yun;Qi, Zhong-Quan
间充质干细胞（MSC）负调节免疫特性。诱导多能干细胞（iPSC）衍生的MSC是MSC的替代来源。然而，iPSC-MSC在体内对T细胞表型的影响仍不清楚。我们使用肾被膜下注射建立了iPSC-MSC移植的宿主抗移植物反应小鼠模型。在体内和体外研究了Th 1、Th 2、调节性T细胞（Treg）和Th 17表型及其细胞因子。半胱天冬酶的作用和可溶性因子参与骨髓间充质干细胞的影响进行了检查。我们发现iPSC-MSC移植物导致小鼠中更多的细胞存活和更少的炎性细胞浸润。iPSCMSC移植抑制T细胞增殖，降低Th 1和Th 2表型和细胞因子，上调Th 17和Treg亚群。此外，iPSC-MSCs抑制caspase 3和8的切割，抑制caspase下调Th 1，Th 2反应，上调Th 17，Treg反应。使用蛋白质阵列测定可溶性因子，发现TGF-β 1/2/3、IL-10和MCP-1在iPSC-MSC中高度表达。可溶性因子的施用降低了Thl/2应答，上调了Treg应答并抑制了半胱天冬酶的切割。我们的研究结果表明，iPSC-MSC调节T细胞反应作为iPSC-MSC分泌的上述可溶性因子的组合作用的结果。这些因子通过抑制半胱天冬酶的裂解来抑制T细胞应答。这些数据为基于iPSC-MSC对T细胞应答的潜在免疫调节作用提供了新的免疫调节机制。
Mesenchymal stem cells (MSCs) negatively modulate immune properties. Induced pluripotent stem cells (iPSCs)-derived MSCs are alternative source of MSCs. However, the effects of iPSC-MSCs on T cells phenotypes in vivo remain unclear. We established an iPSC-MSC-transplanted host versus graft reaction mouse model using subcapsular kidney injection. Th1, Th2, regulatory T cells (Treg), and Th17 phenotypes and their cytokines were investigated in vivo and in vitro. The role of caspases and the soluble factors involved in the effects of MSCs were examined. We found that iPSC-MSC grafts led to more cell survival and less infiltration of inflammatory cells in mice. iPSCMSC transplantation inhibited T cell proliferation, decreased Thl and Th2 phenotypes and cytokines, upregulated Th17 and Treg subsets. Moreover, iPSC-MSCs inhibited the cleavage of caspases 3 and 8 and inhibition of caspases downregulated Th1, Th2 responses and upregulated Th17, Treg responses. Soluble factors were determined using protein array and TGF-beta 1/2/3, IL-10, and MCP-1 were found to be highly expressed in iPSC-MSCs. The administration of the soluble factors decreased Thl/2 response, upregulated Treg response and inhibited the cleavage of caspases. Our results demonstrate that iPSC-MSCs regulate T cell responses as a result of a combined action of the above soluble factors secreted by iPSC-MSCs. These factors suppress T cell responses by inhibiting the cleavage of caspases. These data provide a novel immunomodulatory mechanism for the underlying iPSC-MSC-based immunomodulatory effects on T cell responses.