BMSCs-derived miR-223-containing exosomes contribute to liver protection in experimental autoimmune hepatitis
BMSCs-derived miR-223-containing exosomes contribute to liver protection in experimental autoimmune hepatitis
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BMSCs 衍生的含有 miR-223 的外泌体有助于实验性自身免疫性肝炎的肝脏保护
DOI：
10.1016/j.molimm.2017.11.008
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发表时间：
2018-01-01
影响因子：
3.6
通讯作者：
Chen, Yong-ping
中科院分区：
文献类型：
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作者：
Chen, Lu;Lu, Feng-bin;Chen, Yong-ping
自身免疫性肝炎是一种肝脏慢性炎症性疾病，有可能发展为肝纤维化。最近的证据表明，骨髓间充质干细胞(BMSCs)可能通过外体发挥其治疗作用。此外，miR-223在BMSCs中高表达，在自身免疫性疾病中发挥重要作用。因此，本研究探讨了骨髓间充质干细胞和miR-223对小鼠和肝细胞的保肝作用。用肝抗原5100建立小鼠自身免疫性肝炎模型，用脂多糖和三磷酸腺苷建立肝细胞损伤模型。实验前分别用前miR-223感染BMSCs和用miR-223抑制剂转染BMSCs。用超速离心法分离骨髓干细胞的外切体。通过血清ALT、AST水平及肝组织学检查评价肝损伤程度。炎性细胞因子检测炎症反应，乳糖酶脱氢酶检测细胞死亡。BMSCs-exo和BMSCs-exo(miR-223(+))均能显著逆转S100或LPS/ATP诱导的小鼠肝细胞损伤。同时，BMSCs-exo和BMSCs-exo(miR-223(+))也在蛋白和mRNA水平下调了细胞因子NLRP3和caspase-1的表达。此外，BMSCs-exo(miR-223(+))逆转了BMSCs-exo和BMSCs-exo(miR-223(+))在小鼠AIH和肝细胞中的作用。综上所述，骨髓干细胞来源的外切体对实验性自身免疫性肝炎的肝损伤具有保护作用，其机制可能与外切体miR-223对NLRP3和caspase-1的调节有关。
Autoimmune hepatitis is a chronic inflammatory disease in the liver with potential to the development of liver fibrosis. Recent evidences suggest that bone marrow derived mesenchymal stem cells (BMSCs) may exert its therapeutic activity through exosomes. Moreover, miR-223 is highly expressed in BMSCs and plays an important role in autoimmune diseases. Therefore, in this study, hepatoprotective role of BMSCs and miR-223 was investigated in both mice and hepatocytes. Liver antigen 5100 was used to establish autoimmune hepatitis model in mice while LPS and ATP were used to establish cell injury model in hepatocyte. Before the experiments, BMSCs were infected with pre-miR-223 and transfected with miR-223 inhibitor respectively. Exosomes from bone marrow stem cells were isolated by ultracentrifugation. Liver injury was evaluated by serum levels of ALT and AST as well as liver histology. Inflammation and cell death were examined by inflammatory cytokines and lactase dehydrogenase respectively. Both BMSCs-exo and BMSCs-exo(miR-223(+)) significantly reversed either S100 or LPS/ATP induced injury in mice and hepatocytes. Meanwhile, the expressions of cytokines, NLRP3 and caspase-1 were also downregulated by BMSCs-exo and BMSCs-exo(miR-223(+)) at both protein and mRNA levels in mice and hepatocytes. Moreover, BMSCs-exo(miR-223(+)) reverses the effects of BMSCs-exo and BMSCs-exo(miR-223(+)) in mouse AIH and in hepatocytes. In conclusion, bone marrow stem cell derived exosomes can protect liver injury in an experimental model of autoimmune hepatitis and the mechanism could be related to exosomal miR-223 regulation of NLRP3 and caspase-1.