Rapamycin reverses the senescent phenotype and improves immunoregulation of mesenchymal stem cells from MRL/lpr mice and systemic lupus erythematosus patients through inhibition of the mTOR signaling pathway.
Rapamycin reverses the senescent phenotype and improves immunoregulation of mesenchymal stem cells from MRL/lpr mice and systemic lupus erythematosus patients through inhibition of the mTOR signaling pathway.
复制标题
雷帕霉素通过抑制 mTOR 信号通路来逆转衰老表型并改善 MRL/lpr 小鼠和系统性红斑狼疮患者间充质干细胞的免疫调节。
DOI：
10.18632/aging.100925
复制
发表时间：
2016-05
期刊：
影响因子：
--
通讯作者：
Cheng C
中科院分区：
文献类型：
--
作者：
Gu Z;Tan W;Ji J;Feng G;Meng Y;Da Z;Guo G;Xia Y;Zhu X;Shi G;Cheng C
我们发现来自SLE患者的骨髓间充质干细胞(BM-MSCs)具有衰老行为，并参与了SLE的发病机制。本研究旨在探讨雷帕霉素(RapA)对MRL/LPR小鼠和SLE患者骨髓间充质干细胞衰老和免疫调节能力的影响及其机制。细胞形态、衰老相关β-半乳糖苷酶(SA-β-GAL)染色、F-肌动蛋白染色检测细胞衰老情况。BM-MSCs与纯化的CD4+T细胞间接共培养。用流式细胞仪检测调节性T(Treg)/辅助性T细胞(Th17)的比例。我们使用小干扰RNA(SiRNA)干扰mTOR的表达，并通过RT-PCR、WB和免疫荧光检测其影响。最后，将经RAPA处理的1×106的SLE BM-MSCs移植给8只16周龄的MRL/LPR小鼠，治疗12周。我们证明RAPA可以减轻狼疮性肾炎的临床症状，延长MRL/LPR小鼠的存活时间。RAPA通过抑制mTOR信号通路逆转了MRL/LPR小鼠和SLE患者MSCs的衰老表型并改善了免疫调节。经RAPA处理的SLE患者的BM-MSCs移植后，在MRL/LPR小鼠中观察到明显的治疗效果。
We have shown that bone marrow (BM)-derived mesenchymal stem cells (BM-MSCs) from SLE patients exhibit senescent behavior and are involved in the pathogenesis of SLE. The aim of this study was to investigate the effects of rapamycin (RAPA) on the senescences and immunoregulatory ability of MSCs of MRL/lpr mice and SLE patients and the underlying mechanisms. Cell morphology, senescence associated β-galactosidase (SA-β-gal) staining, F-actin staining were used to detect the senescence of cells. BM-MSCs and purified CD4+ T cells were co-cultured indirectly. Flow cytometry was used to inspect the proportion of regulatory T (Treg) /T helper type 17 (Th17). We used small interfering RNA (siRNA) to interfere the expression of mTOR, and detect the effects by RT-PCR, WB and immunofluorescence. Finally, 1×106 of SLE BM-MSCs treated with RAPA were transplanted to cure the 8 MRL/lpr mice aged 16 weeks for 12 weeks. We demonstrated that RAPA alleviated the clinical symptoms of lupus nephritis and prolonged survival in MRL/lpr mice. RAPA reversed the senescent phenotype and improved immunoregulation of MSCs from MRL/lpr mice and SLE patients through inhibition of the mTOR signaling pathway. Marked therapeutic effects were observed in MRL/lpr mice following transplantation of BM-MSCs from SLE patients pretreated with RAPA.