羊膜间充质干细胞来源的细胞外囊泡改善大鼠肝脏炎症和纤维化
Extracellular Vesicles from Amnion-Derived Mesenchymal Stem Cells Ameliorate Hepatic Inflammation and Fibrosis in Rats.
作者信息
Ohara Masatsugu, Ohnishi Shunsuke, Hosono Hidetaka, Yamamoto Koji, Yuyama Kohei, Nakamura Hideki, Fu Qingjie, Maehara Osamu, Suda Goki, Sakamoto Naoya
机构信息
Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo 0608638, Japan.
Laboratory of Biomembrane and Biofunctional Chemistry, Graduate School of Advanced Life Science, Hokkaido University, Sapporo 0600810, Japan.
出版信息
Stem Cells Int. 2018 Dec 24;2018:3212643. doi: 10.1155/2018/3212643. eCollection 2018.
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 2 mL/kg 50% carbon tetrachloride (CCl) twice a week for six weeks. AMSC-EVs were intravenously injected at weeks 3 and 4 in rats with NASH (15 g/kg) and at week 3 in rats with liver fibrosis (20 g/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 .
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- () , interleukin- () and , and transforming growth factor- () . Furthermore, AMSC-EVs significantly decreased fiber accumulation, KC number, and hepatic stellate cell (HSC) activation in rats with liver fibrosis. , 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.
背景
目前尚无获批用于治疗肝纤维化和非酒精性脂肪性肝炎（NASH）的药物，NASH是纤维化的晚期阶段，已迅速成为肝硬化的主要病因。因此，需要开发抗炎和抗纤维化疗法。基于间充质干细胞（MSC）的疗法在各种器官的再生医学中已得到广泛研究，据报道，该疗法可通过旁分泌作用在NASH中实现治疗效果。细胞外囊泡（EVs）包括细胞释放的多种囊泡，其功能与MSC相似。我们在此研究了羊膜来源的间充质干细胞（AMSCs）释放的细胞外囊泡对NASH和肝纤维化大鼠的治疗作用。
方法
通过4周高脂饮食（HFD）诱导NASH，通过每周两次腹腔注射2 mL/kg 50%四氯化碳（CCl）持续六周诱导肝纤维化。在患有NASH的大鼠第3周和第4周静脉注射AMSC-EVs（15 g/kg），在患有肝纤维化的大鼠第3周静脉注射（20 g/kg）。通过定量逆转录聚合酶链反应和免疫组织化学评估炎症和纤维化程度。研究了AMSC-EVs对炎症和纤维化反应的影响。
结果
AMSC-EVs显著减少了NASH大鼠肝脏中库普弗细胞（KCs）的数量以及肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）和白细胞介素-6（IL-6）等炎性细胞因子的mRNA表达水平，以及转化生长因子-β（TGF-β）。此外，AMSC-EVs显著减少了肝纤维化大鼠的纤维堆积、KC数量和肝星状细胞（HSC）活化。此外，AMSC-EVs显著抑制KC和HSC活化，并抑制脂多糖（LPS）/Toll样受体4（TLR4）信号通路。
结论
AMSC-EVs改善了NASH和肝纤维化大鼠模型中的炎症和纤维化形成，可能是通过减弱HSC和KC活化实现的。AMSC-EV给药应被视为慢性肝病的一种新治疗策略。
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