Epidermal growth factor stimulates exosomal microRNA‐21 derived from mesenchymal stem cells to ameliorate aGVHD by modulating regulatory T cells
Epidermal growth factor stimulates exosomal microRNA‐21 derived from mesenchymal stem cells to ameliorate aGVHD by modulating regulatory T cells
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DOI：
10.1096/fj.201900847rrrr
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发表时间：
2020-04
期刊：
影响因子：
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通讯作者：
Haojie Zhu;Lingqiong Lan;Yuxin Zhang;Qiuru Chen;Yanling Zeng;Xiao-feng Luo;Jinhua Ren;Shaozhen Chen-Shaoz
中科院分区：
文献类型：
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作者：
Haojie Zhu;Lingqiong Lan;Yuxin Zhang;Qiuru Chen;Yanling Zeng;Xiao-feng Luo;Jinhua Ren;Shaozhen Chen-Shaoz
调节性T细胞（Regulatory T cells，Tcells）是CD 4 + T细胞的一个亚群，可对包括急性移植物抗宿主病（acute graft versus host disease，aGVHD）在内的同种异体免疫反应发挥抑制作用，多种microRNA参与了GVHD的病理生理过程。因此，我们在本研究中旨在表征表皮生长因子（EGF）刺激的microRNA-21（miR-21）在aGVHD小鼠模型中调节骨髓间充质干细胞（BMSC）的功能相关性。我们首先分离和培养BMSCs和TCFs。然后，我们通过功能获得和丧失方法检测了miR-21敲低或过表达以及EGF对BMSCs细胞活性以及PTEN、Foxp 3、AKT磷酸化和c-jun磷酸化程度的影响。结果显示，miR-21促进BMSCs的增殖、侵袭和迁移。此外，BMSC来源的外泌体中的miR-21抑制PTEN，但增强Tcells中的AKT磷酸化和Foxp 3表达。此外，EGF增强c-jun磷酸化以提高miR-21表达。此外，EGF显著增加了骨髓间充质干细胞在aGVHD小鼠模型中的功效，表现为IFN-γ表达减少和器官损伤减轻。此外，EGF处理促进了BMSC处理的aGVHD小鼠中Tcells的Foxp 3表达。综上所述，EGF诱导BMSCs来源的外泌体miR-21表达，这增强了Foxp 3在TCFs中的表达，从而提高了BMSCs对aGVHD的治疗效果。
Regulatory T cells (Tregs), a subset of CD4+ T cells, may exert inhibitory effects on alloimmune responses including acute graft‐versus‐host disease (aGVHD), and several microRNAs are implicated in the pathophysiological process of GVHD. Therefore, we aimed in the present study to characterize the functional relevance of epidermal growth factor (EGF)‐stimulated microRNA‐21 (miR‐21) in regulating bone marrow‐derived mesenchymal stem cells (BMSCs) in a mouse model of aGVHD. We first isolated and cultured BMSCs and Tregs. Then, we examined effects of miR‐21 knockdown or overexpression and EGF on cell activities of BMSCs and the expression of PTEN, Foxp3, AKT phosphorylation, and extent of c‐jun phosphorylation by gain‐ and loss‐of‐function approaches. The results showed that miR‐21 promoted the proliferation, invasion, and migration of BMSCs. Furthermore, miR‐21 in BMSCs‐derived exosomes inhibited PTEN, but enhanced AKT phosphorylation and Foxp3 expression in Tregs. In addition, EGF enhanced c‐jun phosphorylation to elevate the miR‐21 expression. Furthermore, EGF significantly increased the efficacy of BMSCs in a mouse model of aGVHD, manifesting in reduced IFN‐γ expression and lesser organ damage. Moreover, EGF treatment promoted the Foxp3 expression of Tregs in BMSCs‐treated aGVHD mice. Taken together, EGF induced the BMSCs‐derived exosomal miR‐21 expression, which enhanced Foxp3 expression in Tregs, thereby improving the therapeutic effect of BMSCs on aGVHD.