Yin Lab

  • Hepatic Biliary Cells

    Hepatic biliary cells, which line the bile ducts, are targets of liver injury, but also orchestrate liver repair.  During development, both hepatocytes and hepatic biliary cells derive from bipotential hepatoblasts.  Hepatic biliary cells undergo extensive morphogenesis to form a complex network of intrahepatic biliary ducts. This network functions to drain the bile produced by hepatocytes to the intestine.  Defects in the formation and morphogenesis of intrahepatic biliary network are responsible for many human congenital liver diseases.  However, our understanding of the molecular mechanisms regulating the development of this network remains very limited.

    In zebrafish, hepatic biliary cells are responsive to Notch signaling and thus can be easily visualized in a Notch reporter line Tg(Tp1bglob:GFP).  Using this tool, we characterized the sox9b mutants that fail to assemble a functional intrahepatic biliary network.  As a result, the adult mutants exhibit cholestasis associated with hepatic cyst formation and fibrosis.  We continue analyzing the molecular and cellular mechanisms underlying the biliary defects in sox9b mutants. 

    Using the Notch reporter line, we conducted a forward genetic screen and identified other mutants that are defective in hepatic biliary cell differentiation or morphogenesis.  Studying these mutants will help us better understand the cell biology of hepatic biliary cells.  Our work in zebrafish will also bring novel insights into our understanding of human biliary diseases, which may translate into novel therapies.

 
  • biliary-visual1-450

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    biliary-visual1-450
    Hepatic biliary ducts in wild-type and sox9b mutant zebrafish at 120 hours post fertilization. These two images are three-dimensional reconstruction of confocal z-stacks scanning through the liver.  Hepatic biliary cells are labeled by Tg(Tp1bglob:GFP) expression (green).  Hepatic canaliculi are labeled by BSEP antibody staining (red).  The hepatic biliary cells in the mutants are clustered together and fail to form the complex network as seen in the wild type.
  • biliary-visual2-450

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    biliary-visual2-450
    Adult sox9b mutants develop cholestasis associated with fibrosis, duct proliferation, and dilation in both the liver and pancreas. (A–B) Dissection of the digestive system of 5 month-old wild-type (A) and sox9b homozygous mutant (B) fish reveals a green mutant liver and pancreas reflecting the accumulation of bile in both organs. Anterior to the top. (C–D) Hematoxylin-and-eosin staining of histological cross-sections of wild-type (C) and sox9b mutant (D) digestive tracts shows abnormal duct morphology in the mutant liver and pancreas.  Higher magnifications of liver (C’–D’) reveal dilated ducts surrounded by fibrotic tissue (pink staining in D’ labeled as ‘‘f’’) in both organs in sox9b mutant. Li, liver; Pa, pancreas; I, intestine.