Extracellular Vesicles from Amnion-Derived Mesenchymal Stem Cells Ameliorate Hepatic Inflammation and Fibrosis in Rats
Extracellular Vesicles from Amnion-Derived Mesenchymal Stem Cells Ameliorate Hepatic Inflammation and Fibrosis in Rats
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DOI：
10.1155/2018/3212643
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发表时间：
2018-01-01
影响因子：
4.3
通讯作者：
Sakamoto, Naoya
中科院分区：
文献类型：
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作者：
Ohara, Masatsugu;Ohnishi, Shunsuke;Sakamoto, Naoya
背景目前还没有批准用于肝纤维化和非酒精性脂肪性肝炎（NASH）的药物治疗，非酒精性脂肪性肝炎是纤维化的晚期阶段，已迅速成为肝硬化的主要原因。因此，需要开发抗炎和抗纤维化疗法。基于间充质干细胞（MSC）的治疗，已在各种器官的再生医学中得到广泛研究，据报道可以通过旁分泌作用在NASH中实现治疗效果。细胞外囊泡（EV）包括由细胞释放的各种囊泡，其实现与MSC的功能类似的功能。我们在此研究了来自骨髓间充质干细胞（AMSC）的EV在患有NASH和肝纤维化的大鼠中的治疗效果。方法.采用高脂饮食（HFD）诱导大鼠NASH模型，腹腔注射50%四氯化碳（CCl 4）2 mL/kg，每周2次，共6周。在NASH大鼠中在第3周和第4周静脉注射AMSC-EV（15 g/kg），在肝纤维化大鼠中在第3周静脉注射AMSC-EV（20 g/kg）。用定量逆转录聚合酶链反应和免疫组织化学方法评价炎症和纤维化的程度。在体外研究AMSC-EV对炎症和纤维化反应的影响。结果AMSC-EV可显著降低NASH大鼠肝脏枯否细胞（KCs）数量，降低肿瘤坏死因子（TNF-）、白细胞介素（IL-）1、IL-6和转化生长因子（TGF-）等炎性细胞因子的mRNA表达水平。此外，AMSC-EV显著降低了肝纤维化大鼠的纤维积聚、KC数量和肝星状细胞（HSC）活化。在体外，AMSC-EV显着抑制KC和HSC活化，并抑制脂多糖（LPS）/Toll样受体4（TLR 4）信号通路。结论. AMSC-EV可能通过减弱HSC和KC活化来改善NASH和肝纤维化大鼠模型中的炎症和纤维化。AMSC-EV给药应被视为慢性肝病的一种新的治疗策略。
Background. There are no approved drug treatments for liver fibrosis and nonalcoholic steatohepatitis (NASH), an advanced stage of fibrosis which has rapidly become a major cause of cirrhosis. Therefore, development of anti-inflammatory and antifibrotic therapies is desired. Mesenchymal stem cell- (MSC-) based therapy, which has been extensively investigated in regenerative medicine for various organs, can reportedly achieve therapeutic effect in NASH via paracrine action. Extracellular vesicles (EVs) encompass a variety of vesicles released by cells that fulfill functions similar to those of MSCs. We herein investigated the therapeutic effects of EVs from amnion-derived MSCs (AMSCs) in rats with NASH and liver fibrosis. Methods. NASH was induced by a 4-week high-fat diet (HFD), and liver fibrosis was induced by intraperitoneal injection of 2mL/kg 50% carbon tetrachloride (CCl4) twice a week for six weeks. AMSC-EVs were intravenously injected at weeks 3 and 4 in rats with NASH (15g/kg) and at week 3 in rats with liver fibrosis (20g/kg). The extent of inflammation and fibrosis was evaluated with quantitative reverse transcription polymerase chain reaction and immunohistochemistry. The effect of AMSC-EVs on inflammatory and fibrogenic response was investigated in vitro. Results. AMSC-EVs significantly decreased the number of Kupffer cells (KCs) in the liver of rats with NASH and the mRNA expression levels of inflammatory cytokines such as tumor necrosis factor- (Tnf-) , interleukin- (Il-) 1 and Il-6, and transforming growth factor- (Tgf-) . Furthermore, AMSC-EVs significantly decreased fiber accumulation, KC number, and hepatic stellate cell (HSC) activation in rats with liver fibrosis. In vitro, AMSC-EVs significantly inhibited KC and HSC activation and suppressed the lipopolysaccharide (LPS)/toll-like receptor 4 (TLR4) signaling pathway. Conclusions. AMSC-EVs ameliorated inflammation and fibrogenesis in a rat model of NASH and liver fibrosis, potentially by attenuating HSC and KC activation. AMSC-EV administration should be considered as a new therapeutic strategy for chronic liver disease.