Reactive cholangiocytes differentiate into proliferative hepatocytes with efficient DNA repair in mice with chronic liver injury

Journal of Hepatology
Rita MancoIsabelle A Leclercq

Abstract

Chronic liver diseases are characterized by expansion of the small immature cholangiocytes - a mechanism named ductular reaction (DR) - which have the capacity to differentiate into hepatocytes. We investigated the kinetics of this differentiation, as well as analyzing several important features of the newly formed hepatocytes, such as functional maturity, clonal expansion and resistance to stress in mice with long-term liver damage. We tracked cholangiocytes using osteopontin-iCreERT2 and hepatocytes with AAV8-TBG-Cre. Mice received carbon tetrachloride (CCl4) for >24 weeks to induce chronic liver injury. Livers were collected for the analysis of reporter proteins, cell proliferation and death, DNA damage, and nuclear ploidy; hepatocytes were also isolated for RNA sequencing. During liver injury we observed a transient DR and the differentiation of DR cells into hepatocytes as clones that expanded to occupy 12% of the liver parenchyma by week 8. By lineage tracing, we confirmed that these new hepatocytes derived from cholangiocytes but not from native hepatocytes. They had all the features of mature functional hepatocytes. In contrast to the exhausted native hepatocytes, these newly formed hepatocytes had higher proliferative ...Continue Reading

Citations

Sep 25, 2019·Cells·Stefaan VerhulstLeo A van Grunsven
Apr 3, 2020·Journal of Molecular Cell Biology·Lulu Sun, Lijian Hui
Sep 20, 2019·Nature Metabolism·Shani Ben-MosheShalev Itzkovitz
May 24, 2020·Cells·Charlotte LefortPatrice D Cani
Aug 17, 2020·Experimental & Molecular Medicine·Juhoon SoDonghun Shin
Oct 20, 2020·Annual Review of Physiology·Konstantinos-Dionysios AlysandratosDarrell N Kotton
Jan 27, 2021·Cellular and Molecular Gastroenterology and Hepatology·Deepthi Y TulasiAdam D Gracz
Mar 19, 2021·Frontiers in Cell and Developmental Biology·Luigi Aloia
May 21, 2019·The American Journal of Pathology·Laure-Alix ClerbauxIsabelle A Leclercq
Dec 15, 2020·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Kyounghwa JungDonghun Shin
May 12, 2021·Annual Review of Biomedical Engineering·Yaron BramRobert E Schwartz
Apr 27, 2021·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Sarah McCarronTobias D Raabe
Sep 25, 2020·Cell Stem Cell·Victoria L GaddStuart J Forbes
Jan 7, 2022·Cell Regeneration·Wenjuan Pu, Bin Zhou

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