Hepatoblast-like Cells Populate the Adult p53 Knockout Mouse Liver: Evidence for a Hyperproliferative, Maturation-arrested Stem Cell Compartment

Although p53 regulates the cell cycle and apoptosis, gross embryonic development is normal in the p53 knockout (-/-) mouse, In this study, we comprehensively assessed liver development in p53 -/- mice (from embryonic day 15 to adult) for evidence of a cell cycle-induced perturbation in differentiation, Liver cell proliferation in the embryo and newborn is similar in p53 -/- and +/+ mice; in contrast, -/- adult hepatocytes divide at twice the rate of wild types. Developmental expression patterns of liver-specific markers that are up-regulated (e,g., phosphoenolpyruvate carboxykinase and aldolase B) and down-regulated (e,g., cu-fetoprotein) are similar. Therefore, embryonic and perinatal liver development is normal in the absence of p53, However, the p53 -/- adult liver displays small blast-like cells, the majority being hepatic and some lymphoid, These cells appear in periportal regions and can infiltrate the parenchyma, The hepatic blast-like cells express both mature and immature liver markers, suggesting that differentiation of the liver stem cell compartment is blocked.