Cholangiocytes act as facultative liver stem cells during impaired hepatocyte regeneration
Open accessAbstract
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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Hepatocyte replenishment can occur via conversion of cholangiocytes during severe liver injury.
“Hepatocyte replenishment can occur via conversion of cholangiocytes during severe liver injury12,13”
From Multimodal decoding of human liver regeneration (2024) · cites this paper as [12]
Reprogramming of differentiated cells into progenitor-like cells is an important injury-repair paradigm independent of adult stem cells in various epithelial tissues in mammals.
“The reprogramming of differentiated cells into progenitor-like cells has recently been discovered as an important injury-repair paradigm independent of adult stem cells in a variety of epithelial tissues in mammals, 1 such as the lung, 2 intestine, 3 pancreas, 4 and liver.5,6”
From Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers (2023) · cites this paper as [5]
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Lineage Tracing Reveals the Bipotency of SOX9+ Hepatocytes during Liver Regeneration
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The Intestinal Epithelium – Fluid Fate and Rigid Structure From Crypt Bottom to Villus Tip
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Alternative splicing rewires Hippo signaling pathway in hepatocytes to promote liver regeneration
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Calcium Signaling in Liver Injury and Regeneration
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The evolving definition of salivary gland stem cells
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Cell of origin in biliary tract cancers and clinical implications
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Generation and Differentiation of Adult Tissue-Derived Human Thyroid Organoids
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Diploid hepatocytes drive physiological liver renewal in adult humans
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Next-Generation Liver Medicine Using Organoid Models
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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
- Venue
- Nature
- Published
- 2017-07-12
- Volume
- 547
- Issue
- 7663
- Pages
- 350-354
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- 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
- 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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