Cited by 533Liver physiology and pathologyTissue Engineering and Regenerative MedicineDrug-Induced Hepatotoxicity and Protection

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Cholangiocytes act as facultative liver stem cells during impaired hepatocyte regeneration

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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, Boulter, Luke, Forbes, Stuart J.·2017·Nature

DOI 10.1038/nature23015PMC PMC5522613

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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.

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Authors: Raven, A., Lu, W.-Y., Man, T. Y., Ferreira-Gonzalez, S., O’Duibhir, E., Dwyer, B. J., Thomson, J. P., Meehan, R. R., Bogorad, R., Koteliansky, V., Kotelevtsev, Y., ffrench-Constant, C., Boulter, L., & Forbes, S. J.
Affiliations: MRC Centre for Regenerative Medicine (GB)
Institute of Genetics and Cancer (GB)
Koch Institute for Integrative Cancer Research At MIT (US)
Skolkovo Institute of Science and Technology (RU)
Corresponding author: Forbes, Stuart J.
ORCID: Raven, Alexander
Lu, Wei-Yu
Man, Tak Yung
O’Duibhir, Eoghan
Dwyer, Benjamin J.
Thomson, John P.
Meehan, Richard R.
Bogorad, Roman
Kotelevtsev, Yuri
Boulter, Luke
Forbes, Stuart J.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2017-07-12
Volume: 547
Issue: 7663
Pages: 350-354
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature23015
PMC: PMC5522613
OpenAlex: W2734880494
Cited by: 533
References: 30
Citations by year: 2026: 32 · 2025: 47 · 2024: 47 · 2023: 62 · 2022: 56 · 2021: 80 · 2020: 79 · 2019: 62 · 2018: 61 · 2017: 7
FWCI: 35.32
Type: journal article
Language: en
Update notices: erratum (2018-03-15)
Open access: bronze
doi.org
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
RePEc: Research Papers in Economics (submittedVersion)
University of Birmingham Research Portal (University of Birmingham) (submittedVersion, other-oa)
Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
UEA Digital Repository (University of East Anglia) (submittedVersion)
Funders: UK Regenerative Medicine Platform (K026666, MR/K026666/1, MR/L012766/1)
Medical Research Council (MR/L012766/1, MR/K026666, MC_PC_U127574433, MR/K017047/1, MR/K026666/1)
Topics: Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
Keywords: cholangiocytes, hepatocyte regeneration, liver injury, beta1 integrin, p21, cell cycle inhibition, ductular reaction, hepatocyte proliferation, chronic liver disease, lineage tracing
MeSH terms: Animals, Bile Ducts, Intrahepatic, Female, Liver, Liver Diseases, Liver Regeneration, Male, Mice, Inbred C57BL, Stem Cells, Integrin beta1, Cell Lineage, Hepatocytes, Cell Proliferation, Mice

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Cholangiocytes act as facultative liver stem cells during impaired hepatocyte regeneration

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