ABSTRACT
Hepatic stellate cells (HSCs), as the most important stromal cells in the liver microenvironment, play crucial roles in hepatic fibrosis, hepatocellular carcinoma, liver regeneration and fetal liver development after transdifferentiating into myofibroblasts (MFs). Transforming growth factor ß1 (TGF-ß1), as an important polyergic cytokine, is involved in HSCs activation process. However, the specific mechanisms of HSCs transdifferentiation process are not clearly demonstrated. Here we added exogenous recombinant TGF-ß1 protein and transforming growth factor ß receptor 1 (TGF-ßR1) inhibitor SB431542 into mouse HSCs to detect the detailed impact of TGF-ß1 signaling on HSCs activation. TGF-ß1 signaling significantly increased phosphorylated (P)-Smad2/3 level and promoted Smad2/3 translocation from the cytoplasm to the nucleus, which also caused transdifferentiation of HSCs into MFs. Importantly, TGF-ß1 signaling also resulted in high expression of Notch pathway markers Notch1, Jagged1, Hes1 in HSCs. In contrast, expression of those above markers in mouse HSCs were obviously decreased after hampering TGF-ß1 signaling via TGF-ßR1 inhibitor SB431542. To further examine the effect of Notch pathway on HSCs activation process, TGF-ß1-stimulated HSCs and control HSCs were treated with or without LY450139, a specific inhibitor of Notch pathway. LY450139 evidently decreased the expression of Notch1 and MFs marker α-smooth muscle actin (α-SMA) expression in HSCs. These above results may provide a novel insight that TGF-ß1 signaling controls HSCs activation process through regulating the expression of Notch pathway markers.
