Polyploid Hepatocytes Facilitate Adaptation and Regeneration to Chronic Liver Injury
Open accessAbstract
The liver contains diploid and polyploid hepatocytes (tetraploid, octaploid, etc.), with polyploids comprising ≥90% of the hepatocyte population in adult mice. Polyploid hepatocytes form multipolar spindles in mitosis, which lead to chromosome gains/losses and random aneuploidy. The effect of aneuploidy on liver function is unclear, and the degree of liver aneuploidy is debated, with reports showing aneuploidy affects 5% to 60% of hepatocytes. To study relationships among liver polyploidy, aneuploidy, and adaptation, mice lacking E2f7 and E2f8 in the liver (LKO), which have a polyploidization defect, were used. Polyploids were reduced fourfold in LKO livers, and LKO hepatocytes remained predominantly diploid after extensive proliferation. Moreover, nearly all LKO hepatocytes were euploid compared with control hepatocytes, suggesting polyploid hepatocytes are required for production of aneuploid progeny. To determine whether reduced polyploidy impairs adaptation, LKO mice were bred onto a tyrosinemia background, a disease model whereby the liver can develop disease-resistant, regenerative nodules. Although tyrosinemic LKO mice were more susceptible to morbidities and death associated with tyrosinemia-induced liver failure, they developed regenerating nodules similar to control mice. Analyses revealed that nodules in the tyrosinemic livers were generated by aneuploidy and inactivating mutations. In summary, we identified new roles for polyploid hepatocytes and demonstrated that they are required for the formation of aneuploid progeny and can facilitate adaptation to chronic liver disease.
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E2f7 and E2f8, as well as polyploidy, suppress tumorigenesis.
“E2f7 and E2f8, as well as polyploidy, are known to suppress tumorigenesis (43–46).”
From Wnt signaling regulates hepatocyte cell division by a transcriptional repressor cascade (2022) · cites this paper as [45]
E2f7 and E2f8 as well as polyploidy are known to suppress tumorigenesis.
“while E2f7 and E2f8 as well as polyploidy are known to suppress tumorigenesis (Kent et al. 2016;Moreno et al. 2021;Wilkinson et al. 2019;Zhang et al. 2018).”
From Hepatocyte Cell Cycle Progression Depends on a Transcriptional Repressor Cascade Downstream of Wnt Signaling (2021) · cites this paper as Wilkinson et al. 2019
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“comprises polyploid or aneuploid hepatocytes, thus, creating increased genetic diversity (64, 65).”
Background
- Authors
- Wilkinson, P. D., Alencastro, F., Delgado, E. R., Leek, M. P., Weirich, M. P., Otero, P. A., Roy, N., Brown, W. K., Oertel, M., & Duncan, A. W.
- Affiliations
- University of Pittsburgh (US)
- Corresponding author
- Duncan, Andrew W.
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2019-06
- Volume
- 189
- Issue
- 6
- Pages
- 1241-1255
- ISSN
- 0002-9440 (ISSN-L)
- PMC
- PMC6547059
- OpenAlex
- W2932483334
- Cited by
- 60
- References
- 0
- Citations by year
- 2026: 7 · 2025: 4 · 2024: 4 · 2023: 7 · 2022: 11 · 2021: 15 · 2020: 10 · 2019: 2
- FWCI
- 6.06
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- American Journal Of Pathology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (R01 DK103645)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Surgery › Organ Transplantation Techniques and Outcomes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Keywords
- aneuploidy, liver regeneration, chronic liver injury, tyrosinemia, E2F7, E2F8, polyploidization, liver failure, loss-of-function mutations
- MeSH terms
- Adaptation, Physiological, Animals, Liver Regeneration, Polyploidy, Repressor Proteins, Mice, Inbred NOD, Mice, Knockout, Hepatocytes, E2F7 Transcription Factor, Mice, Lung Injury, Gene Knockdown Techniques
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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