间充质干细胞调控EMT机制改善胆道闭锁胆管纤维化的实验研究

项目名称： 间充质干细胞调控EMT机制改善胆道闭锁胆管纤维化的实验研究

项目编号： No.81460118

项目类型： 地区科学基金项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 张守华

作者单位： 江西省儿童医院

项目金额： 47万元

中文摘要： 近年，主要认为胆道闭锁（biliary atresia, BA）是由病毒感染介导的自身免疫性疾病，表现为破坏性胆道炎症性病变，最终导致胶原沉着和肝纤维化，然而其发病机制尚未阐明。研究表明TNF-α、TGF等免疫相关细胞因子可诱导胆道上皮发生EMT，使其转变为肌成纤维细胞，最终引起胆管纤维化。基于我们前期采用肝脏干细胞逆转不同背景的肝纤维化的基础上，发现间充质干细胞（MSCs）具有调节免疫功能（下调TGF）和定向分化为胆管细胞和肝细胞的功能，改善肝脏微环境，我们推测：间充质干细胞可通过调控EMT而改善胆道闭锁引起的胆管纤维化。本课题拟首先利用胆道闭锁动物模型评价MSCs治疗胆道闭锁的效果；其次利用细胞共培养、Western blot等方法观察MSCs在胆管上皮细胞EMT中的作用；最后运用细胞RNA干扰等方法明确MSCs通过HGF/c-Met通路调控EMT，为临床治疗BA提供新思路和理论依据。

中文关键词： 胆道闭锁；间充质干细胞；上皮-间叶转化

英文摘要： Recent years' study shows that biliary atresia (BA) is autoimmune disease which triggered by viral infection, and the the main performance is biliary tract destructive inflammation. However, its pathogenesis has not been elucidated, and the collagen continue composuring which leading liver fibrosis.Research showed that TNF-α,TGF and some other immune related cytokines could induce biliary epithelium EMT,changed it into a muscle fibroblasts, resulting in bile duct fibrosis. On the basis of preliminary research of hepatic stem cells reversing liver fibrosis,we found that the mesenchymal stem cells(MSCs) can differentiate into hepatocytes and bile duct cells, at the same time, which has the function of regulating immune function(down-regulated TGF) and improving liver microenvironment. We hypothesize that: MSCs could affect the EMT by regulating immune related factors and improve biliary fibrosis caused by BA. This topic first observe therapeutic effect of the MSCs for the treatment of BA using of BA animal model and then study the role of MSCs in EMT by using cell culture, Western blot and so on methods.Finally clarify that mechanism of the role of MSCs in EMT by HGF/c-Met pathway using the method of RNA interference and provide new ideas and theoretical basis for clinical treatment.

英文关键词： biliary atresia;mensenchymal stem cells;epithelial-mesenchymal transition