FoxA2通过阻断和逆转肝脏前体细胞EMT而抑制肝纤维化进展的机制研究

肝脏前体细胞是肝脏损伤修复的关键细胞，但转化生长因子(TGF-b1)会使其发生上皮-间质转化(EMT)成为肌成纤维细胞。我们的研究发现表皮细胞生长因子(EGF)可通过ERK1/2和Akt途径阻断和逆转前体细胞的EMT，且叉头蛋白FoxA2是此过程中变化显著的转录因子，推测FoxA2是阻断和逆转肝脏前体细胞EMT抑制肝纤维化的关键因子。本研究首先利用EGF通路抑制剂探讨EGF阻断和逆转前体细胞EMT过程中调控FoxA2表达与功能的信号分子；然后采用过表达和抑制FoxA2表达的前体细胞检测FoxA2与EMT、增殖分化基因和转录因子的相互作用，明确FoxA2干预前体细胞EMT转变的机制；最后将过表达和抑制FoxA2表达的前体细胞移植到大鼠中，并制备四氯化碳肝纤维化与纤维消解模型，探讨干预前体细胞的FoxA2对纤维化进展与消解的影响。期待为阐明肝脏前体细胞在纤维化进展和消解中的作用提供依据。

As progeny of hepatic stem cells, hepatic progenitor cells emerge and expand in periportal areas of the injured liver when the regenerative capability of hepatocytes and cholangiocytes are impaired, thus serving as the major cells for liver injury repair and tissue regeneration. Previous studies show that TGF-β1, the major fibrogenic factor in the liver, may induce hepatic progenitor cells to display fibroblastic phenotype through epithelial-mesenchymal transition (EMT), and chronic and constant treatment of TGF-β1 further makes them obtaining tumor initiating cell properties. We find that epithelial growth factor (EGF) appears to be the specific cytokine with an opposite function to TGF-β1 allowing for suppressing and reversing EMT of hepatic progenitors through phosphorylation of ERK1/2 and Akt. Furthermore, the expression of Forkhead Box Protein A2 (FoxA2) reduced significantly in TGF-β1-induced EMT process and recovered in EGF-regulated EMT-reversing process. Therefore, we hypothesize FoxA2 might be the major transcription factor involving the EMT blocking and reversing process of hepatic progenitors, which may slow down the progression of liver fibrosis. In this study, We are going to find the mechanism of FoxA2 on EMT transition and liver fibrogenesis of hepatic progenitors from the following three aspects. First, we would like to confirm the signal pathway of EGF on the transcription, expression and function of FoxA2 by EGF receptor inhibitor, ERK1/2 inhibitor and Akt inhibitor. Secondly, we are going to use FoxA2 over-expressing and FoxA2 siRNA hepatic progenitors to find the blocking and reversing effects of FoxA2 on EMT transition of hepatic progenitors and the interactions of FoxA2 with the gene promoters and the transcription factors involved in EMT transition, cell proliferation and differentiation. Finally, we will transplant FoxA2 over-expressing and FoxA2 siRNA hepatic progenitors into rat, and induce liver fibrosis by CCl4 and fibrosis regression by withdraw CCl4 in order to find the contribution of hepatic progenitors with different FoxA2 expressing status to liver fibrosis. We hope this study could provide evidence for understanding the behavior of hepatic progenitors in the progression and regression of liver fibrosis and reversion of liver fibrosis.