Human bone marrow mesenchymal stem cells-derived exosomes alleviate liver fibrosis through the Wnt/β-catenin pathway
Human bone marrow mesenchymal stem cells-derived exosomes alleviate liver fibrosis through the Wnt/β-catenin pathway
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DOI：
10.1186/s13287-019-1204-2
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发表时间：
2019-03-18
影响因子：
7.5
通讯作者：
Xie, Feng
中科院分区：
文献类型：
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作者：
Rong, Xiaoli;Liu, Junzhi;Xie, Feng
间充质干细胞（MSCs）越来越多地被用于肝纤维化的治疗。外泌体具有与其亲本细胞相似的功能；然而，它们是安全有效的无细胞试剂，具有可控和可预测的结果。在这项研究中，我们研究了人骨间充质干细胞来源的外泌体（hBM-MSCs-Ex）治疗肝纤维化的治疗潜力和潜在的分子机制。方法建立8周ccl4诱导的大鼠肝纤维化模型，然后给药4周hBM-MSCs-Ex。分析结果的组织病理学、肝功能和炎症细胞因子。此外，我们通过western blotting检测Wnt/-catenin信号通路相关基因的表达，研究hBM-MSCs-Ex在肝星状细胞（HSCs）和肝纤维化组织中的抗纤维化机制。结果hBM-MSCs-Ex在体内有效缓解肝纤维化，包括减少胶原积累，增强肝功能，抑制炎症，增加肝细胞再生。此外，通过测量胶原面积、Ishak纤维化评分、MDA水平、IL-1、IL-6， hBM-MSCs- ex对肝纤维化的治疗效果明显大于hBM-MSCs。此外，我们发现hBM-MSCs-Ex抑制了HSCs和肝纤维化组织中Wnt/-catenin通路组分（PPAR、Wnt3a、Wnt10b、-catenin、WISP1、Cyclin D1）、-SMA和胶原I的表达。结论hBM-MSCs-Ex治疗可通过Wnt/-catenin通路抑制HSC活化，从而改善ccl4诱导的肝纤维化。
BackgroundMesenchymal stem cells (MSCs) are increasingly being applied as a therapy for liver fibrosis. Exosomes possess similar functions to their parent cells; however, they are safe and effective cell-free reagents with controllable and predictable outcomes. In this study, we investigated the therapeutic potential and underlying molecular mechanism for human bone mesenchymal stem cells-derived exosomes (hBM-MSCs-Ex) in the treatment of liver fibrosis.MethodsWe established an 8-week CCl4-induced rat liver fibrosis model, after which, we administered hBM-MSCs-Ex in vivo for 4weeks. The resulting histopathology, liver function, and inflammatory cytokines were analyzed. In addition, we investigated the anti-fibrotic mechanism of hBM-MSCs-Ex in hepatic stellate cells (HSCs) and liver fibrosis tissue, by western blotting for the expression of Wnt/-catenin signaling pathway-related genes.ResultsIn vivo administration of hBM-MSCs-Ex effectively alleviated liver fibrosis, including a reduction in collagen accumulation, enhanced liver functionality, inhibition of inflammation, and increased hepatocyte regeneration. Moreover, based on measurement of the collagen area, Ishak fibrosis score, MDA levels, IL-1, and IL-6, the therapeutic effect of hBM-MSCs-Ex against liver fibrosis was significantly greater than that of hBM-MSCs. In addition, we found that hBM-MSCs-Ex inhibited the expression of Wnt/-catenin pathway components (PPAR, Wnt3a, Wnt10b, -catenin, WISP1, Cyclin D1), -SMA, and Collagen I, in both HSCs and liver fibrosis tissue.ConclusionsThese results suggest that hBM-MSCs-Ex treatment could ameliorate CCl4-induced liver fibrosis via inhibition of HSC activation through the Wnt/-catenin pathway.