The liver possesses a remarkable regenerative capacity based partly on the ability of hepatocytes to re-enter the cell cycle and divide to replace damaged cells. This capability is substantially reduced upon chronic damage, but it is not clear if this is a cause or consequence of liver disease. Here, we investigate whether blocking hepatocyte division using two different mouse models affects physiology as well as clinical liver manifestations like fibrosis and inflammation. We find that in P14 Cdk1^Liv-/- mice, where the division of hepatocytes is abolished, polyploidy, DNA damage, and increased p53 signaling are prevalent. Cdk1^Liv-/- mice display classical markers of liver damage two weeks after birth, including elevated ALT, ALP, and bilirubin levels, despite the lack of exogenous liver injury. Inflammation was further studied using cytokine arrays, unveiling elevated levels of CCL2, TIMP1, CXCL10, and IL1-Rn in Cdk1^Liv-/- liver, which resulted in increased numbers of monocytes. Ablation of CDK2-dependent DNA re-replication and polyploidy in Cdk1^Liv-/- mice reversed most of these phenotypes. Overall, our data indicate that blocking hepatocyte division induces biological processes driving the onset of the disease phenotype. It suggests that the decrease in hepatocyte division observed in liver disease may not only be a consequence of fibrosis and inflammation, but also a pathological cue.

肝脏具有显着的再生能力，部分是基于肝细胞重新进入细胞周期并分裂以替换受损细胞的能力。慢性损伤后，这种能力会大大降低，但尚不清楚这是肝病的原因还是后果。在这里，我们调查使用两种不同的小鼠模型阻断肝细胞分裂是否会影响生理以及诸如肝纤维化和炎症的临床肝脏表现。我们发现在P14 Cdk1 ^Liv-/-小鼠中，肝细胞分裂被废除，多倍体，DNA损伤和增加的p53信号传导普遍存在。Cdk1 ^Liv-/-尽管缺乏外源性肝损伤，小鼠在出生后两周仍表现出经典的肝损伤标志物，包括ALT，ALP和胆红素水平升高。使用细胞因子阵列进一步研究了炎症，发现Cdk1 ^Liv-/-肝脏中CCL2，TIMP1，CXCL10和IL1-Rn的水平升高，导致单核细胞数量增加。Cdk1 ^Liv-/-中依赖CDK2的DNA复制和多倍性的消融小鼠逆转了大多数这些表型。总体而言，我们的数据表明，阻断肝细胞分裂会诱导驱动疾病表型发作的生物学过程。这表明在肝病中观察到的肝细胞分裂的减少不仅是纤维化和炎症的结果，而且是病理学提示。