间充质干细胞调节表观调控因子EZH2治疗肝衰竭的分子机制研究

项目名称： 间充质干细胞调节表观调控因子EZH2治疗肝衰竭的分子机制研究

项目编号： No.81470867

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 蔡伟

作者单位： 上海交通大学

项目金额： 73万元

中文摘要： 肝衰竭是肝脏免疫紊乱及继发大量肝细胞坏死导致的肝损伤。间充质干细胞(MSC)具有多向分化修复组织的能力又具有其它干细胞不具备的免疫调节特性，恰针对肝衰竭病理机制，符合有效治疗肝衰竭的需求。我们既往研究发现MSC是通过诱导调节性树突状细胞(DC)产生，抑制了免疫紊乱导致的肝衰竭，进一步明晰其免疫调控分子机制及损伤修复机制是MSC治疗肝衰竭中亟需解决的重要科学问题。我们前期研究发现急性肝衰竭小鼠肝脏DC及肝干细胞表达的表观调控因子EZH2显著降低，MSC输注后EZH2表达显著升高，并与免疫调控和肝干细胞动员增殖有关。由此，本项目拟以肝衰竭患者标本和疾病模式动物，研究肝衰竭发病中EZH2介导的病理机制；揭示MSC治疗通过调控EZH2，实现抑制免疫紊乱和促进肝干细胞修复损伤的双重作用；阐明MSC治疗肝衰竭的核心机制，形成干预新策略。为临床肝衰竭免疫学诊断新指标和治疗新靶点的建立提供理论和实验依据。

中文关键词： 肝衰竭；间充质干细胞；EZH2；树突状细胞；肝脏干细胞

英文摘要： Liver failure is liver tissue injury mediated by dysfunction of the immune system and the subsequent massive liver cell necrosis. Mesenchymal stem cells (MSC) are multipotent stromal cells with immunomodulatory capacity which could be utilized to treat liver failure. Our previous studies have found that MSC inhibit liver failure by inducing the generation of regulatory dendritic cells (DC). However, the molecular mechanisms by which MSC regulate the immune system and take part in tissue repair during liver failure remain to be resolved. Our preliminary study found that expression of epigenetic regulator EZH2 was significantly reduced in liver DC and hepatic stem cells during acute liver failure. However, MSC transplantation upregulated the expression of EZH2 in both cells which might be associated with immunomodulation and hepatic stem cell activation. Therefore, based on patients with liver failure and animal models, this program aims to investigate the pathological mechanism of EZH2 in promoting liver failure, and reveal the regulatory effect of EZH2 in MSC-based immunomodulation and hepatic stem cell activation. Most importantly, this program trys to uncover the key mechanism by which MSC inhibit liver failure. Altogether, this program aims to provide a novel strategy for the clinical immunological diagnosis and treatment of liver failure.

英文关键词： liver failure;mesenchymal stem cells;EZH2;dendritic cells;hepatic stem cells