中胚层源性细胞转分化获得肝细胞已显示了潜在的应用前景。但外源基因插入的跨胚层诱导存在致瘤风险，且诱导效率低。申请人应用转录因子联合小分子化合物已将人毛囊间充质干细胞（hHF-MSCs）转分化为肝细胞；单独应用小分子化合物诱导，又得到了小鼠源性的内胚层祖细胞，后者经高通量数据分析显示Activin/Nodal受体及Sox17高表达。基于此，本研究拟以hHF-MSCs为转分化起始细胞，单纯利用小分子化合物和细胞因子组合：先经MET过程活化hHF-MSCs，而后用Activin A激活Activin/Nodal-Sox17信号轴跨胚层获得内胚层祖细胞；通过体外实验及动物模型原位确定其向肝细胞和胆管细胞分化的潜能；以Activin/Nodal通路及基因Sox17之间调控网络，探讨hHF-MSCs向内胚层转分化的分子机理。为克服跨胚层障碍、排除致瘤风险，获得可用于肝衰治疗的内胚层祖细胞提供理论基础。

Trans-differentiation of mesodermal-derived cells into hepatocytes has shown potential application prospects. However, the transembryonic induction of exogenous gene insertion has the risk of tumorigenesis, and the efficiency is low. The applicant has trans-differentiated human hair follicle mesenchymal stem cells (hHF-MSCs) into hepatocytes across the germinal layer by transcription factors combined with small molecule compounds. In addition, the high-throughput data of mouse-derived endodermal progenitors induced by small molecule compounds alone showed high expression of Activin/Nodal receptor and Sox17. Based on these, we intend to use hHF-MSCs as trans-differentiation initiating cells, using small molecule compounds and cytokines alone: first, hHF-MSCs will be activated by MET process; second, Activin A will be used to activate Activin/Nodal-Sox17 signal axis to obtain endodermal progenitors across the embryonic layer; then, their differentiation potential into hepatocyte and cholangiocytesis will be detected by in vivo and in vitro experiments; finally, the molecular mechanism of trans-differentiation will be explored through the regulatory network of Activin/Nodal pathway and Sox17 gene. This study will provide a theoretical basis for overcoming the barriers between the layers, eliminat the risk of tumorigenesis and gain endodermal progenitors for the treatment of liver failure.