Loss of hepatocyte cell division leads to liver inflammation and fibrosis


Autoři: Matthew R. Dewhurst aff001;  Jin Rong Ow aff001;  Gözde Zafer aff001;  Noémi K. M. van Hul aff001;  Heike Wollmann aff001;  Xavier Bisteau aff001;  David Brough aff002;  Hyungwon Choi aff001;  Philipp Kaldis aff001
Působiště autorů: Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore aff001;  Lydia Becker Institute of Immunology and Inflammation; and Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, M aff002;  Lydia Becker Institute of Immunology and Inflammation; and Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, M aff002;  Lydia Becker Institute of Immunology and Inflammation; and Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, M aff002;  Lydia Becker Institute of Immunology and Inflammation; and Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, M aff002;  Lydia Becker Institute of Immunology and Inflammation; and Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, M aff002;  Lydia Becker Institute of Immunology and Inflammation; and Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, M aff002;  Lydia Becker Institute of Immunology and Inflammation; and Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, M aff002;  Lydia Becker Institute of Immunology and Inflammation; and Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, M aff002;  Department of Biochemistry, National University of Singapore (NUS), Singapore aff003;  Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore aff004;  Department of Clinical Sciences, Lund University, Clinical Research Centre (CRC), Sweden aff005
Vyšlo v časopise: Loss of hepatocyte cell division leads to liver inflammation and fibrosis. PLoS Genet 16(11): e1009084. doi:10.1371/journal.pgen.1009084
Kategorie: Research Article
doi: 10.1371/journal.pgen.1009084

Souhrn

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.

Klíčová slova:

Cell cycle and cell division – DNA damage – Fatty liver – Fibrosis – Hepatocytes – Liver fibrosis – Mouse models – Polyploidy


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