Tie1+肝脏细胞在肝纤维化进程中的作用、来源、转分化过程及机制研究

肝纤维化是慢性肝病进展的关键步骤，目前尚无任何有效治疗药物。申请人聚焦肝纤维化发生机制和治疗方法研究，发现肝纤维化进程中出现Lgr5+肝组织干细胞，通过诱导该细胞可治疗肝纤维化（Nature Communictions，2017）；发现肝纤维化进程中肝细胞上调LECT2表达，与血管内皮细胞特异性受体Tie1结合调控肝脏血管新生/重构和肝纤维化（Cell，2019）。在上述研究中意外发现，血管内皮细胞特异受体Tie1表达于一群损伤周围的肝细胞，且该群细胞随着肝纤维化进程不断变化，有转分化现象，该Tie1+肝细胞尚未见报道。利用已有的谱系示踪小鼠和条件敲除小鼠申请人将深入研究：肝纤维化进程及损伤修复过程中Tie1+肝细胞的来源、作用、在体转分化及调控机制。本研究将鉴定一群新的细胞类型：Tie1+肝细胞并阐明其作用和机制，为肝纤维化发生机制提供新理论，为治疗肝纤维化提供新靶点和理论依据。

Liver fibrogenesis is a key step during chronic liver disease processing, and its mechanism is poorly understanded. At present, there is no effective treatment drug. We focused on the study of the mechanism and treatment of liver fibrosis. We found that Lgr5+ liver stem cells appeared during liver fibrogenesis, inducing Lgr5+ liver stem cells could treat liver fibrosis (Nature Commun, 2017). During liver fibrogenesis, hepatocytes up-regulated LECT2 expression, LECT2 binded to Tie1 (vascular endothelial cell specific receptor) to regulate liver angiogenesis/remodeling and liver fibrogenesis (Cell, 2019). During the above study, We unexpectedly found that the vascular endothelial cell specific receptor Tie1 was expressed in a population of hepatocytes around the injury, this population of cells changed along with the process of liver fibrosis, and a phenomenon of transdifferentiation of Tie1+ liver cells happened. This population of Tie1+ liver cells has not been reported. We will further investigate the origin, function, transdifferentiation and regulatory mechanism of Tie1+ liver cells in the process of liver fibrosis and damage repair. In this study, we will identify a population of new cell types: Tie1+ liver cells and uncover their roles and mechanisms during liver fibrogenesis. Our study provide a new theory for the mechanism of liver fibrogenesis, and provide new targets and the theoretical base for liver fibrosis therapy.