Dewhurst MR, Ow JR, Zafer G, van Hul NKM, Wollmann H, Bisteau X, et al. (2020) Loss of hepatocyte cell division leads to liver inflammation and fibrosis. PLoS Genet 16(11): e1009084. https://doi.org/10.1371/journal.pgen.1009084
Abstract:
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.
License type:
http://creativecommons.org/licenses/by/4.0/
Funding Info:
The work was supported in part by the Faculty of Medicine, Lund University to PK, the Biomedical Research Council, Agency for Science, Technology and Research (A*STAR) to PK; by SINGA (Singapore International Graduate Award) to GZ; by A*GA (A*STAR Graduate Student Academy; ARAP with University of Manchester) to MRD; by the Biomedical Research Council - Joint Council Office Grant (1231AFG031) to PK; by the National Medical Research Council Singapore, NMRC (NMRC/CBRG/0091/2015) to PK; and by National Research Foundation Singapore grant (NRF2016-CRP001-103) to PK, the Swedish Foundation for Strategic Research Dnr IRC15-0067, and Swedish Research Council, Strategic Research Area EXODIAB, Dnr 2009–1039.