The Characteristics Variation of Hepatic Progenitors after TGF-beta 1-Induced Transition and EGF-Induced Reversion

摘要

Profibrogenesis cytokine, transforming growth factor- (TGF-) beta 1, induces hepatic progenitors experiencing epithelial to mesenchymal transition (EMT) to matrix synthesis cells, even tumor initiating cells. Our previous data found that epidermal growth factor (EGF) blocks and reverses TGF-beta 1-induced transition. The aim of this study is to determine the characteristic changes of hepatic progenitors after TGF-beta 1-induced transition and EGF-induced reversion. Hepatic oval cells, rat hepatic progenitors, were isolated from rats fed a choline-deficient diet supplemented with ethionine. TGF-beta 1-containing medium was used for inducing EMT, while EGF-containing medium was used for reversing EMT. During TGF-beta 1-induced transition and EGF-induced reversion, hepatic oval cells sustained their progenitor cell marker expression, including alpha-fetoprotein, albumin, and cytokeratin-19. The proliferation ability and differentiation potential of these cells were suppressed by TGF-beta 1, while EGF resumed these capacities to the level similar to the control cells. RNA microarray analysis showed that most of the genes with significant changes after TGF-beta 1 incubation were recovered by EGF. Signal pathway analysis revealed that TGF-beta 1 impaired the pathways of cell cycle and cytochrome P450 detoxification, and EGF reverted TGF-beta 1 effects through activating MAPK and PI3K-Akt pathway. EGF reverses the characteristics impaired by TGF-beta 1 in hepatic oval cells, serving as a protective cytokine to hepatic progenitors.