Cholangiocytes act as facultative liver stem cells during impaired hepatocyte regeneration

Raven, Alexander, Lu, Wei Yu, Man, Tak Yung, Ferreira-Gonzalez, Sofia, O'Duibhir, Eoghan, Dwyer, Benjamin J., Thomson, John P., Meehan, Richard R., Bogorad, Roman, Koteliansky, Victor, Kotelevtsev, Yuri, Ffrench-Constant, Charles ORCID: https://orcid.org/0000-0002-5621-3377, Boulter, Luke and Forbes, Stuart J. (2017) Cholangiocytes act as facultative liver stem cells during impaired hepatocyte regeneration. Nature, 547 (7663). pp. 350-354. ISSN 0028-0836

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Abstract

After liver injury, regeneration occurs through self-replication of hepatocytes. In severe liver injury, hepatocyte proliferation is impaired - a feature of human chronic liver disease. It is unclear whether other liver cell types can regenerate hepatocytes. Here we use two independent systems to impair hepatocyte proliferation during liver injury to evaluate the contribution of non-hepatocytes to parenchymal regeneration. First, loss of β1-integrin in hepatocytes with liver injury triggered a ductular reaction of cholangiocyte origin, with approximately 25% of hepatocytes being derived from a non-hepatocyte origin. Second, cholangiocytes were lineage traced with concurrent inhibition of hepatocyte proliferation by β1-integrin knockdown or p21 overexpression, resulting in the significant emergence of cholangiocyte-derived hepatocytes. We describe a model of combined liver injury and inhibition of hepatocyte proliferation that causes physiologically significant levels of regeneration of functional hepatocytes from biliary cells.

Item Type: Article
Additional Information: Funding Information: Work in the laboratory of R.R.M. was supported by the UK Medical Research Council (MRC) (MC-PC-U127574433). This work was supported by the MRC (MR/L012766/1, MR/K017047/1) and the UK Regenerative Medicine Platform (MR/K026666/1).
Uncontrolled Keywords: general,sdg 3 - good health and well-being ,/dk/atira/pure/subjectarea/asjc/1000
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
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Depositing User: LivePure Connector
Date Deposited: 15 Jul 2022 14:31
Last Modified: 21 Jul 2022 11:39
URI: https://ueaeprints.uea.ac.uk/id/eprint/86239
DOI: 10.1038/nature23015

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