Cellular and molecular gastroenterology and hepatology · 2026
Mesothelin/Mucin 16 Signaling in Activated Portal Fibroblasts Drives the Development of Cholestatic Fibrosis and Hepatocellular Carcinoma in Aged Female Multidrug Resistance Protein 2 Knockout Mice.
СтатьяПоддержка исследования: вне правительства СШАПоддержка NIH: внешняя программаНазвание и аннотация: Перевод в очереди
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Sakane Sadatsugu, Nishio Takahiro, Fuji Hiroaki, Park Se Yong, Ishizuka Kei, Miciano Charlene, Kimura Yusuke, Hosseini Mojgan, Diggle Karin, Zhang Vivian, Lee Wonseok, Kim Hyun Young, Liu Xiao, Wang Allen, Brenner David A, Kisseleva Tatiana
Аннотация
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 mesothelin (Msln)-mucin 16 (Muc16)- Thy-1 cell surface antigen (Thy-1) signaling in activated portal fibroblasts (aPFs), is unknown.
METHODS: The role of aPFs/mesenchymal cells in the pathogenesis of cholestatic fibrosis and hepatocellular carcinoma (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 GPC3+SOX9+AFP+ HCC than age-matched male littermates. Deletion of Msln or Muc16 ameliorated cholestatic fibrosis, inflammation and HCC in Mdr2-/-Msln-/- and Mdr2-/-Muc16-/- mice, whereas Mdr2-/- and Mdr2-/-Thy-1-/- mice exhibited similar phenotypes and developed severe fibrosis and HCC. Aged Mdr2-/-Msln-/- and Mdr2-/-Muc16-/- mice developed fewer HCCs and of smaller sizes. Ductular proliferation and hepatocyte and cholangiocyte senescence were suppressed in Mdr2-/-Msln-/- and Mdr2-/-Muc16-/- mice, whereas 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 crosstalk 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 patients with HCC and sclerosis cholangitis.
METHODS: The role of aPFs/mesenchymal cells in the pathogenesis of cholestatic fibrosis and hepatocellular carcinoma (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 GPC3+SOX9+AFP+ HCC than age-matched male littermates. Deletion of Msln or Muc16 ameliorated cholestatic fibrosis, inflammation and HCC in Mdr2-/-Msln-/- and Mdr2-/-Muc16-/- mice, whereas Mdr2-/- and Mdr2-/-Thy-1-/- mice exhibited similar phenotypes and developed severe fibrosis and HCC. Aged Mdr2-/-Msln-/- and Mdr2-/-Muc16-/- mice developed fewer HCCs and of smaller sizes. Ductular proliferation and hepatocyte and cholangiocyte senescence were suppressed in Mdr2-/-Msln-/- and Mdr2-/-Muc16-/- mice, whereas 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 crosstalk 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 patients with HCC and sclerosis cholangitis.
Предметные рубрики MeSH
AnimalsMesothelinFemaleCarcinoma, HepatocellularSignal TransductionMice, KnockoutLiver NeoplasmsMiceATP Binding Cassette Transporter, Subfamily BFibroblastsCholestasisGPI-Linked ProteinsCA-125 AntigenMembrane ProteinsHumansMaleDisease Models, AnimalFibrosisATP-Binding Cassette Sub-Family B Member 4Podoplanin