Depletion of β-catenin from mature hepatocytes of mice promotes expansion of hepatic progenitor cells and tumor development

Depletion of beta-catenin impairs regeneration of the rapid turn-over gut epithelial cells, but appears dispensable for that of the slow turn-over mature hepatocytes in mice until 1 y of age. As the life span of mature murine hepatocytes is about 400 d, we studied conditional beta-catenin knockout mice (Alb-Cre;Ctnnb1(flx/flx)) until 20 mo of age to determine the function of beta-catenin in the postnatal liver. beta-catenin was absent from the hepatocytes of beta-catenin knockout mice 4 wk after delivery. From 9 mo of age, hepatocytes were gradually replaced by newly formed beta-catenin-positive hepatocytes, which constituted about 90% of hepatocytes at 18-20 mo of age. This process was accompanied by active proliferation of bile duct/ductule cells. beta-catenin-positive hepatocytes exhibited elevated proliferation activity and expression of progenitor cell markers, but lower albumin and Cre. This might explain their intact beta-catenin protein, and suggest their origins from hepatic progenitor cells. Liver tumors arose spontaneously from beta-catenin-positive cells, and tumorigenesis was accelerated by hepatitis B X protein. These results indicate beta-catenin critical for the regeneration of mature hepatocytes. Failure to regenerate mature hepatocytes results in proliferation of hepatic progenitor cells that are able to maintain liver function but are predisposed to form liver tumors.