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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 CCl<jats:sub>4<\/jats:sub>-induced fibrosis. The present study analyzed the role of transforming growth factor-\u03b2 (TGF-\u03b2) signaling in mesothelial-mesenchymal transition (MMT) and the fate of MCs during liver fibrosis and its regression. Deletion of TGF-\u03b2 type II receptor ( Tgfbr2) gene in cultured MCs suppressed TGF-\u03b2-mediated myofibroblastic conversion. Conditional deletion of Tgfbr2 gene in MCs reduced the differentiation of MCs to HSCs and myofibroblasts in the BDL and CCl<jats:sub>4<\/jats:sub> models, respectively, indicating that the direct TGF-\u03b2 signaling in MCs is responsible to MMT. After BDL and CCl<jats:sub>4<\/jats:sub> treatment, MC-derived HSCs and myofibroblasts were distributed near the liver surface and the thickness of collagen was increased in Glisson's capsule beneath the liver surface. Fluorescence-activated cell sorting analysis revealed that MC-derived HSCs and myofibroblasts store little vitamin A lipids and have fibrogenic phenotype in the fibrotic livers. MCs contributed to 1.4 and 2.0% of activated HSCs in the BDL and CCl<jats:sub>4<\/jats:sub> models, respectively. During regression of CCl<jats:sub>4<\/jats:sub>-induced fibrosis, 20% of MC-derived myofibroblasts survived in the liver and deactivated to vitamin A-poor HSCs. 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