Liver maturation deficiency in p57Kip2−/− mice occurs in a hepatocytic p57Kip2 expression-independent manner

Fetal hepatic stem/progenitor cells, hepatoblasts, are highly proliferative cells and the source of both hepatocytes and cholangiocytes. In contrast, mature hepatocytes have a low proliferative potency and high metabolic functions. Cell proliferation is regulated by cell cycle-related molecules. However, the correlation between cell cycle regulation and hepatic maturation are still unknown. To address this issue, we revealed that the cell cycle inhibitor p57Kip2 was expressed in the hepatoblasts and mesenchymal cells of fetal liver in a spatiotemporal manner. In addition, we found that hepatoblasts in p57Kip2−/− mice were highly proliferative and had deficient maturation compared with those in wild-type (WT) mice. However, there were no remarkable differences in the expression levels of cell cycle- and bipotency-related genes except for Ccnd2. Furthermore, p57Kip2−/− hepatoblasts could differentiate into mature hepatocytes in p57Kip2−/− and WT chimeric mice, suggesting that the intrinsic activity of p57Kip2 does not simply regulate hepatoblast maturation.