mTOR inhibition improves the immunomodulatory properties of human bone marrow mesenchymal stem cells by inducing COX-2 and PGE(2).
mTOR inhibition improves the immunomodulatory properties of human bone marrow mesenchymal stem cells by inducing COX-2 and PGE(2).
复制标题
mTOR 抑制通过诱导 COX-2 和 PGE 改善人骨髓间充质干细胞的免疫调节特性(2)
DOI：
10.1186/s13287-017-0744-6
复制
发表时间：
2017-12-29
影响因子：
7.5
通讯作者：
Huang H
中科院分区：
文献类型：
--
作者：
Wang B;Lin Y;Hu Y;Shan W;Liu S;Xu Y;Zhang H;Cai S;Yu X;Cai Z;Huang H
骨髓间充质干细胞（MSC）是有前途的候选人，用于治疗各种炎症性疾病，由于其深刻的免疫调节特性。然而，MSC的免疫抑制能力需要通过炎症微环境激活，这可能会因为免疫原性增加而对治疗效果产生负面影响。在这里，我们探讨哺乳动物雷帕霉素靶蛋白（mTOR）信号传导对MSC免疫抑制能力的作用，以及其对炎症微环境中免疫原性的影响。将人骨髓间充质干细胞与活化的人外周血单个核细胞、CD 4 + T细胞和小鼠脾细胞共培养，以评价其免疫抑制功能。免疫抑制因子通过定量实时聚合酶链反应（PCR）、蛋白质印迹和酶联免疫吸附试验（ELISA）进行评估。流式细胞术检测细胞主要组织相容性复合物（MHC）的表达。短发夹状RNA（sh RNA）用于下调MSC中的结节性硬化症复合物（TSC）2、TSC 1和环氧合酶（考克斯）-2。使用雷帕霉素抑制mTOR信号传导增强了MSC的免疫抑制功能，而长期暴露于雷帕霉素则没有。免疫抑制功能的增强不依赖于炎症微环境，主要通过上调考克斯-2和前列腺素E2（PGE 2）的表达来实现。此外，mTOR抑制不影响MSC的免疫原性。然而，通过干扰素（IFN）-γ上调的MHC II类分子的表达被mTOR抑制减弱，而TSC 2敲低具有相反的效果。这些结果表明，mTOR信号通路调节MSC的免疫生物学，短期暴露于雷帕霉素可能是一种新的方法，以提高基于MSC的治疗效果。本文的在线版本（doi：10.1186/s13287-017-0744-6）包含补充材料，可供授权用户使用。
Bone marrow mesenchymal stem cells (MSCs) are promising candidates for the treatment of various inflammatory disorders due to their profound immunomodulatory properties. However, the immunosuppressive capacity of MSCs needs activation by an inflammatory microenvironment, which may negatively impact the therapeutic effect because of increased immunogenicity. Here we explore the role of mammalian target of rapamycin (mTOR) signaling on the immunosuppressive capacity of MSCs, and its impact on immunogenicity in the inflammatory microenvironment. Human bone marrow MSCs were cocultured with activated human peripheral blood mononuclear cells, CD4+ T cells, and mouse splenocytes to evaluate the immunosuppressive function. Immunosuppressive factors were assessed by quantitative real-time polymerase chain reaction (PCR), Western blot, and enzyme-linked immunosorbent assay (ELISA). The expression of major histocompatibility complex (MHC) was detected by flow cytometry. Short hairpin (sh)RNA was used to downregulate tuberous sclerosis complex (TSC)2, TSC1, and cyclooxygenase (COX)-2 in MSCs. Inhibition of mTOR signaling using rapamycin enhanced the immunosuppressive functions of MSCs, while prolonged exposure to rapamycin did not. The enhancement of the immunosuppressive function was independent of the inflammatory microenvironment, and occurred mainly through the upregulation of COX-2 and prostaglandin-E2 (PGE2) expression. Furthermore, mTOR inhibition did not impact the immunogenicity of MSCs. However, the upregulated expression of MHC class II molecules by interferon (IFN)-γ was attenuated by mTOR inhibition, whereas TSC2 knockdown had the opposite effect. These results reveal that the mTOR signaling pathway regulates MSC immunobiology, and short-term exposure to rapamycin could be a novel approach to improve the MSC-based therapeutic effect. The online version of this article (doi:10.1186/s13287-017-0744-6) contains supplementary material, which is available to authorized users.
登录
查看更多内容
影响因子：
4.8
作者：
Larson, Yan;Liu, Jianyu;Gao, Tianyan
通讯作者：
Gao, Tianyan
影响因子：
2.5
作者：
Stagg, J.;Galipeau, J.
通讯作者：
Galipeau, J.
影响因子：
5.2
作者：
Martin, Sally K.;Fitter, Stephen;Zannettino, Andrew C. W.
通讯作者：
Zannettino, Andrew C. W.
影响因子：
16
作者：
Sarbassov, DD;Ali, SM;Sabatini, DM
通讯作者：
Sabatini, DM
影响因子：
5.3
作者：
Julien, Louis-Andre;Carriere, Audrey;Roux, Philippe P.
通讯作者：
Roux, Philippe P.