CRISPLD2 in Hepatic Fibrogenesis and Cholangiocellular Carcinoma Progression

Studies in the past have shown that bile ductular hyperplasia correlates with the degree of hepatic fibrosis and that myofibroblasts are a major component of cholangiocellular carcinoma (CCA). However, the mechanism of cross‐talk between bile ductular epithelial cells and hepatic stellate cells during hepatic fibrogenesis and CCA progression was not established. In this study, we identified CRISPLD2, a secretory protein reported to be critical for epithelial morphogenesis during lung and kidney development, as one of the top differentially up‐regulated genes in the liver of a mouse model of nonalcoholic steatohepatitis (NASH). A combined in situ hybridization, histochemistry, immunohistochemistry and image analysis suggested that CRISPLD2 mRNA was expressed in hepatic stellate cells accompanying bile ductules and collagen fibers in the liver of mouse model of NASH and human cirrhotic liver. Furthermore, cancer‐associated myofibroblasts express CRISPLD2 mRNA in human cholangiocarcinoma tissues. These data suggest that CRISPLD2 may play a role in the branching morphogenesis of biliary epithelial cells and participate in hepatic fibrogenesis and cholangiocellular carcinoma progression. Further characterization of the role of CRISPLD2 is important as it may serve a novel candidate for targeted therapy and/or biomarker for hepatic fibrosis and CCA.