Role of TGF-β signaling in differentiation of mesothelial cells to vitamin A-poor hepatic stellate cells in liver fibrosis

Mesothelial cells (MCs) form a single layer of the mesothelium and cover the liver surface. A previous study demonstrated that, upon liver injury, MCs migrate inward from the liver surface and give rise to hepatic stellate cells (HSCs) in biliary fibrosis induced by bile duct ligation (BDL) or myofibroblasts in CCl4-induced fibrosis. The present study analyzed the role of transforming growth factor-β (TGF-β) signaling in mesothelial-mesenchymal transition (MMT) and the fate of MCs during liver fibrosis and its regression. Deletion of TGF-β type II receptor (Tgfbr2) gene in cultured MCs suppressed TGF-β-mediated myofibroblastic conversion. Conditional deletion of Tgfbr2 gene in MCs reduced the differentiation of MCs to HSCs and myofibroblasts in the BDL and CCl4 models, respectively, indicating that the direct TGF-β signaling in MCs is responsible to MMT. After BDL and CCl4 treatment, MC-derived HSCs and myofibroblasts were distributed near the liver surface and the thickness of collagen was increased in G...