Msln/Muc16 signaling in activated Portal Fibroblasts drives the development of cholestatic fibrosis and HCC in aged female Mdr2 mice.
[BACKGROUND & AIMS] The contribution of activated Hepatic Stellate Cells (aHSCs) to cholestatic fibrosis and cancer is well documented, but the role of portal fibroblasts (PFs), and especially Msln-Mu
APA
Sakane S, Nishio T, et al. (2026). Msln/Muc16 signaling in activated Portal Fibroblasts drives the development of cholestatic fibrosis and HCC in aged female Mdr2 mice.. Cellular and molecular gastroenterology and hepatology, 101785. https://doi.org/10.1016/j.jcmgh.2026.101785
MLA
Sakane S, et al.. "Msln/Muc16 signaling in activated Portal Fibroblasts drives the development of cholestatic fibrosis and HCC in aged female Mdr2 mice.." Cellular and molecular gastroenterology and hepatology, 2026, pp. 101785.
PMID
41967578
Abstract
[BACKGROUND & AIMS] The contribution of activated Hepatic Stellate Cells (aHSCs) to cholestatic fibrosis and cancer is well documented, but the role of portal fibroblasts (PFs), and especially Msln-Muc16-Thy-1 signaling in aPFs, is unknown.
[METHODS] The role of activated PFs (aPFs)/mesenchymal cells in the pathogenesis of cholestatic fibrosis and HCC was studied in aged (16 months old) multidrug resistance protein 2 knockout (Mdr2) mice, which mimic primary biliary cholangitis with biliary fibrosis.
[RESULTS] Aged female Mdr2 mice were more susceptible to cholestatic fibrosis and inflammation and developed 4 fold more adenomas and GPC3SOX9AFP HCC than age-matched male littermates. Deletion of Msln or Muc16 ameliorated cholestatic fibrosis, inflammation and HCC in Mdr2Msln and Mdr2Muc16 mice, while Mdr2 and Mdr2Thy-1 mice exhibited similar phenotypes and developed severe fibrosis and HCC. Aged Mdr2Msln and Mdr2Muc16 mice developed fewer HCCs and of smaller sizes. Ductular proliferation, and hepatocyte and cholangiocyte senescence were suppressed in Mdr2Msln and Mdr2Muc16 mice, while hepatocyte regeneration was markedly improved. Msln- and Muc16-deficient aPFs exhibited a less fibrogenic and inflammatory phenotype, and downregulated expression of Col1a2, Col3a1, Tgfβ1, MMP3, Cxcl9, Clcl7, Lgals1, and MMP2/3. The lack of MMP3 in Msln aPFs was linked to increased hepatocyte proliferation. Based on in vitro studies, MMP3-mediated shedding of hepatic HGFR (c-Met) was identified as one of the mechanisms by which aPFs suppress HGF-c-Met-induced phosphorylation of AKT, ERK, p38, resulting in proliferation of primary human hepatocytes. In turn, proliferation of MMP3-stimulated human hepatocytes was restored in the presence of MMP3 inhibitor.
[CONCLUSIONS] These findings demonstrate that aPFs mediate the cross-talk between cholangiocytes and hepatocytes, regulate hepatocyte functions, and that Msln-Muc16 signaling in aPFs is pathogenic for cholestatic fibrosis and HCC. Msln and Muc16 may become novel targets for anti-fibrotic therapy and HCC patients with sclerosis cholangitis.
[METHODS] The role of activated PFs (aPFs)/mesenchymal cells in the pathogenesis of cholestatic fibrosis and HCC was studied in aged (16 months old) multidrug resistance protein 2 knockout (Mdr2) mice, which mimic primary biliary cholangitis with biliary fibrosis.
[RESULTS] Aged female Mdr2 mice were more susceptible to cholestatic fibrosis and inflammation and developed 4 fold more adenomas and GPC3SOX9AFP HCC than age-matched male littermates. Deletion of Msln or Muc16 ameliorated cholestatic fibrosis, inflammation and HCC in Mdr2Msln and Mdr2Muc16 mice, while Mdr2 and Mdr2Thy-1 mice exhibited similar phenotypes and developed severe fibrosis and HCC. Aged Mdr2Msln and Mdr2Muc16 mice developed fewer HCCs and of smaller sizes. Ductular proliferation, and hepatocyte and cholangiocyte senescence were suppressed in Mdr2Msln and Mdr2Muc16 mice, while hepatocyte regeneration was markedly improved. Msln- and Muc16-deficient aPFs exhibited a less fibrogenic and inflammatory phenotype, and downregulated expression of Col1a2, Col3a1, Tgfβ1, MMP3, Cxcl9, Clcl7, Lgals1, and MMP2/3. The lack of MMP3 in Msln aPFs was linked to increased hepatocyte proliferation. Based on in vitro studies, MMP3-mediated shedding of hepatic HGFR (c-Met) was identified as one of the mechanisms by which aPFs suppress HGF-c-Met-induced phosphorylation of AKT, ERK, p38, resulting in proliferation of primary human hepatocytes. In turn, proliferation of MMP3-stimulated human hepatocytes was restored in the presence of MMP3 inhibitor.
[CONCLUSIONS] These findings demonstrate that aPFs mediate the cross-talk between cholangiocytes and hepatocytes, regulate hepatocyte functions, and that Msln-Muc16 signaling in aPFs is pathogenic for cholestatic fibrosis and HCC. Msln and Muc16 may become novel targets for anti-fibrotic therapy and HCC patients with sclerosis cholangitis.