Mesenchymal stem cell-derived exosomes protect against liver fibrosis via delivering miR-148a to target KLF6/STAT3 pathway in macrophages.
Mesenchymal stem cell-derived exosomes protect against liver fibrosis via delivering miR-148a to target KLF6/STAT3 pathway in macrophages.
复制标题
间充质干细胞衍生的外泌体通过将 miR-148a 递送至巨噬细胞中的 KLF6/STAT3 通路来预防肝纤维化
DOI：
10.1186/s13287-022-03010-y
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发表时间：
2022-07-20
影响因子：
7.5
通讯作者：
中科院分区：
文献类型：
--
作者：
尽管越来越多的证据表明间充质干细胞(MSCs)具有治疗肝纤维化的潜能，但其潜在的机制仍不清楚。目前，MSC衍生的外切体(MSC-EXOS)被广泛认为是细胞间通讯的重要信使。本研究旨在探讨MSC-EXOS对肝纤维化的治疗作用，并探讨其作用机制。方法采用四氯化碳诱导大鼠肝纤维化模型，静脉注射MSCs或MSC-EXOS评价其治疗效果。分析组织病理学、纤维化程度、炎症反应和巨噬细胞极化情况。用RAW264.7和BMDM细胞研究MSC-EXOS对巨噬细胞极化的调节作用。然后，通过RNA测序筛选出介导MSC-EXOS治疗作用的关键miRNA，并进行了实验验证。通过荧光素酶报告基因分析、生物信息学分析和Western blotting分析，进一步阐明了靶基因和下游信号转导途径。结果MSCs的抗肝纤维化作用主要依赖于其分泌的外切体，移植后可见其进入肝脏循环。此外，还发现MSC-EXOS可调节巨噬细胞表型，调节肝脏炎症微环境，修复损伤。从机制上讲，RNA测序表明，富含MSC-EXOS的miR-148A靶向Kruppel样因子6(KLF6)，通过抑制STAT3途径抑制促炎巨噬细胞和促进抗炎巨噬细胞。结论MSC-EXOS通过转导miR-148A，通过KLF6/STAT3信号转导调节肝内巨噬细胞功能，具有抗肝纤维化作用，为肝纤维化提供了潜在的治疗靶点。
BackgroundDespite emerging evidence on the therapeutic potential of mesenchymal stem cells (MSCs) for liver fibrosis, the underlying mechanisms remain unclear. At present, MSC-derived exosomes (MSC-EXOs) are widely accepted as crucial messengers for intercellular communication. This study aimed to explore the therapeutic effects of MSC-EXOs on liver fibrosis and identify the mechanisms underlying the action of MSC-EXOs.MethodsCarbon tetrachloride was used to induce a liver fibrosis model, which was intravenously administered with MSCs or MSC-EXOs to assess treatment efficacy. The resulting histopathology, fibrosis degree, inflammation and macrophage polarization were analyzed. RAW264.7 and BMDM cells were used to explore the regulatory effects of MSC-EXOs on macrophage polarization. Then, the critical miRNA mediating the therapeutic effects of MSC-EXOs was screened via RNA sequencing and validated experimentally. Furthermore, the target mRNA and downstream signaling pathways were elucidated by luciferase reporter assay, bioinformatics analysis and western blot.ResultsMSCs alleviated liver fibrosis largely depended on their secreted exosomes, which were visualized to circulate into liver after transplantation. In addition, MSC-EXOs were found to modulate macrophage phenotype to regulate inflammatory microenvironment in liver and repair the injury. Mechanically, RNA-sequencing illustrates that miR-148a, enriched in the MSC-EXOs, targets Kruppel-like factor 6 (KLF6) to suppress pro-inflammatory macrophages and promote anti-inflammatory macrophages by inhibiting the STAT3 pathway. Administration of miR-148a-enriched MSC-EXOs or miR-148a agomir shows potent ameliorative effects on liver fibrosis.ConclusionsThese findings suggest that MSC-EXOs protect against liver fibrosis via delivering miR-148a that regulates intrahepatic macrophage functions through KLF6/STAT3 signaling and provide a potential therapeutic target for liver fibrosis.
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影响因子：
23.9
作者：
Caplan AI;Correa D
通讯作者：
Correa D
源自低氧基于嗅觉粘膜间充质干细胞的细胞外囊泡通过miR-612增强了血管生成。
影响因子：
10.2
作者：
Ge L;Xun C;Li W;Jin S;Liu Z;Zhuo Y;Duan D;Hu Z;Chen P;Lu M
通讯作者：
Lu M
影响因子：
29.4
作者：
Lee, Chien-Wei;Chen, Yu-Fan;Lee, Oscar K.
通讯作者：
Lee, Oscar K.
影响因子：
4.8
作者：
Date, Dipali;Das, Riku;Mahabeleshwar, Ganapati H.
通讯作者：
Mahabeleshwar, Ganapati H.
影响因子：
7.5
作者：
Rong, Xiaoli;Liu, Junzhi;Xie, Feng
通讯作者：
Xie, Feng