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骨髓间充质干细胞来源的细胞外囊泡 miR-34a 通过细胞周期蛋白 I/ATM/ATR/p53 轴减轻类风湿关节炎炎症。

miR-34a in extracellular vesicles from bone marrow mesenchymal stem cells reduces rheumatoid arthritis inflammation via the cyclin I/ATM/ATR/p53 axis.

机构信息

Center for Precision Medicine, Anhui No. 2 Provincial People's Hospital, Hefei, China.

Department of Medical Laboratory Science, The Fifth People's Hospital of Wuxi, Nanjing Medical University, Wuxi, China.

出版信息

J Cell Mol Med. 2021 Feb;25(4):1896-1910. doi: 10.1111/jcmm.15857. Epub 2021 Jan 19.

DOI:10.1111/jcmm.15857
PMID:33465281
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7882978/
Abstract

Extracellular vesicles (Evs) participate in the development of rheumatoid arthritis (RA), but the mechanisms remain unclear. This study aimed to determine the mechanism by which microRNA-34a (miR-34a) contained in bone marrow mesenchymal stem cell (BM-MSC)-derived Evs functions in RA fibroblast-like synoviocytes (RA-FLSs). BM-MSC-derived Evs and an Evs inhibitor were extracted. A rat model of RA was established. miR-34a gain- and loss-of-function experiments were performed, and the inflammation in rat synovial fluid and tissues was detected. The role of miR-34a in RA-FLSs was also measured in vitro. The target gene of miR-34a was predicted using the online software TargetScan and identified using a dual-luciferase reporter gene assay, and the activation of the ATM/ATR/p53 signalling pathway was assessed. BM-MSC-derived Evs mainly elevated miR-34a expression, which reduced RA inflammation in vivo and inhibited RA-FLS proliferation and resistance to apoptosis in vitro, while inhibited miR-34a expression enhanced RA development. In addition, miR-34a could target cyclin I to activate the ATM/ATR/p53 signalling pathway, thus inhibiting abnormal RA-FLS growth and RA inflammation. Our study showed that miR-34a contained in BM-MSC-derived Evs could reduce RA inflammation by inhibiting the cyclin I/ATM/ATR/p53 signalling pathway.

摘要

细胞外囊泡 (EVs) 参与类风湿关节炎 (RA) 的发生发展，但具体机制尚不清楚。本研究旨在探讨骨髓间充质干细胞 (BM-MSCs) 来源的 EVs 中含有的 microRNA-34a (miR-34a) 在 RA 成纤维样滑膜细胞 (RA-FLSs) 中的作用机制。提取 BM-MSC 来源的 EVs 和 EVs 抑制剂。建立 RA 大鼠模型。进行 miR-34a 功能获得和功能丧失实验，检测大鼠滑膜液和组织中的炎症。在体外测量 miR-34a 在 RA-FLSs 中的作用。使用在线软件 TargetScan 预测 miR-34a 的靶基因，并通过双荧光素酶报告基因检测进行鉴定，评估 ATM/ATR/p53 信号通路的激活情况。BM-MSC 来源的 EVs 主要上调 miR-34a 的表达，体内降低 RA 炎症，体外抑制 RA-FLS 增殖和抗凋亡，而抑制 miR-34a 表达则促进 RA 的发展。此外，miR-34a 可以靶向细胞周期蛋白 I 激活 ATM/ATR/p53 信号通路，从而抑制异常的 RA-FLS 生长和 RA 炎症。本研究表明，BM-MSC 来源的 EVs 中含有的 miR-34a 通过抑制细胞周期蛋白 I/ATM/ATR/p53 信号通路减轻 RA 炎症。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6772/7882978/1825d2170b74/JCMM-25-1896-g008.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6772/7882978/1825d2170b74/JCMM-25-1896-g008.jpg
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