Liver maturation deficiency in p57^Kip2-/- mice occurs in a hepatocytic p57^Kip2 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 p57^Kip2 was expressed in the hepatoblasts and mesenchymal cells of fetal liver in a spatiotemporal manner. In addition, we found that hepatoblasts in p57^Kip2-/- 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, p57^Kip2-/- hepatoblasts could differentiate into mature hepatocytes in p57^Kip2-/- and WT chimeric mice, suggesting that the intrinsic activity of p57^Kip2 does not simply regulate hepatoblast maturation.