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 Cdk1Liv-/- mice, where the division of hepatocytes is abolished, polyploidy, DNA damage, and increased p53 signaling are prevalent. Cdk1Liv-/- 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 Cdk1Liv-/- liver, which resulted in increased numbers of monocytes. Ablation of CDK2-dependent DNA re-replication and polyploidy in Cdk1Liv-/- 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.

Matthew R. Dewhurst

Jin Rong Ow

Gözde Zafer

Noémi K. M. van Hul

Heike Wollmann

Xavier Bisteau

David Brough

Hyungwon Choi

Philipp Kaldis

PLoS Genetics

PLOS GENETICS 由一个国际编辑委员会管理，该委员会由主编 GREG BARSH（哈德逊阿尔法生物技术研究所和斯坦福大学医学院）和 GREG COPENHAVER（北卡罗来纳大学教堂山分校）领导。发表的文章PLOS GENETICS 中的 IN 存档在 PUBMED CENTRAL 中并在 PUBMED 中引用。

PLOS GENETICS is managed by an international editorial board led by editors-in-chief GREG BARSH (Hudson Alpha Institute for Biotechnology and Stanford University School of Medicine) and GREG COPENHAVER (University of North Carolina at Chapel Hill). Articles published in PLOS GENETICS are archived in PUBMED CENTRAL and cited in PUBMED.

《PLoS Genetics》由国际编辑委员会管理，主编为GREG BARSH（哈德逊阿尔法生物技术研究所和斯坦福大学医学院）和GREG COPENHAVER（北卡罗来纳大学教堂山分校）。该期刊发表的文章会在PUBMED CENTRAL进行存档，并在PUBMED中引用。

Loss of hepatocyte cell division leads to liver inflammation and fibrosis

The data indicate that blocking hepatocyte division induces biological processes driving the onset of the disease phenotype, which suggests that the decrease in hepatocytes division observed in liver disease may not only be a consequence of fibrosis and inflammation, but also a pathological cue.

Category	Quartile
生物学	2
生物学, 遗传学	2

Loss of hepatocyte cell division leads to liver inflammation and fibrosis

ivySCI AI Smartly Parses PDF, Answers Researchers' Questions, and Helps You Understand Papers in Seconds

Journal Info