The ploidy conveyor of mature hepatocytes as a source of genetic variation
Open accessAbstract
Mononucleated and binucleated polyploid hepatocytes (4n, 8n, 16n and higher) are found in all mammalian species, but the functional significance of this conserved phenomenon remains unknown. Polyploidization occurs through failed cytokinesis, begins at weaning in rodents and increases with age. Previously, we demonstrated that the opposite event, ploidy reversal, also occurs in polyploid hepatocytes generated by artificial cell fusion. This raised the possibility that somatic 'reductive mitoses' can also happen in normal hepatocytes. Here we show that multipolar mitotic spindles form frequently in mouse polyploid hepatocytes and can result in one-step ploidy reversal to generate offspring with halved chromosome content. Proliferating hepatocytes produce a highly diverse population of daughter cells with multiple numerical chromosome imbalances as well as uniparental origins. Our findings support a dynamic model of hepatocyte polyploidization, ploidy reversal and aneuploidy, a phenomenon that we term the 'ploidy conveyor'. We propose that this mechanism evolved to generate genetic diversity and permits adaptation of hepatocytes to xenobiotic or nutritional injury.
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When polyploid hepatocytes divide they can give rise to aneuploid hepatocytes, causing genetic variation among hepatocytes in mice as well as humans.
“Additionally, when polyploid hepatocytes divide they can give rise to aneuploid hepatocytes, causing genetic variation among hepatocytes in mice as well as humans.32,36”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [32]
The Main Text (page unavailable) reports that dividing mouse polyploid hepatocytes produce aneuploid, genetically diverse daughter cells. It does not show that this process causes genetic variation among human hepatocytes; its human-gene probe was used in mice, and its reference to polyploid hepatocytes across mammals does not establish the claimed human outcome. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAt birth, all hepatocytes are diploid, with accumulation of polyploid hepatocytes, mostly 4n and some 8n, occurring during post-natal development until polyploid hepatocytes account for ∼90% of hepatocytes in rodent livers and 30% in human livers.
“Curiously, at birth, all hepatocytes are diploid, with accumulation of polyploid hepatocytes, mostly 4n and some 8n, occurring during post-natal development (further reviewed in[29], [30], [31]), until polyploid hepatocytes account for ∼90% of hepatocytes in rodent livers and 30% in human livers.[32], [33], [34], [35]”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [32]
The Main Text (page not provided) says hepatocyte polyploidization begins at weaning in rodents and increases with age, and identifies 4n and 8n hepatocytes. It does not give the claimed ∼90% prevalence in rodent livers or 30% in human livers. Its 90 ± 2% figure refers to marker expression in transplanted octaploid cells, not the proportion of polyploid hepatocytes. (LLM, conf=0.87)
Experimental — accuracy not yet measuredThe vast majority of liver chromatin stems from hepatocytes, which are the prominent cell type in the liver and are mostly polyploid.
“In line with the vast majority of the liver chromatin stemming from hepatocytes (which are the prominent cell‐type in the liver and are, moreover, mostly polyploid cells – up to 85% in mice with mainly tetraploid hepatocytes; Duncan et al, 2010)”
From An extended transcription factor regulatory network controls hepatocyte identity (2023) · cites this paper as Duncan et al, 2010
The Main Text (page unavailable) describes polyploid hepatocytes in mammals and discusses their ploidy in mice, supporting the polyploidy portion of the claim. It does not state that hepatocytes supply the vast majority of liver chromatin, that they are the most numerous liver cell type, or that up to 85% of mouse hepatocytes are polyploid and mainly tetraploid. (LLM, conf=0.86)
Experimental — accuracy not yet measured
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- Authors
- Duncan, A. W., Taylor, M. H., Hickey, R. D., Hanlon Newell, A. E., Lenzi, M. L., Olson, S. B., Finegold, M. J., & Grompe, M.
- Affiliations
- Oregon Health & Science University (US)
- Texas Children's Hospital (US)
- ORCID
- Venue
- Nature
- Published
- 2010-09-22
- Volume
- 467
- Issue
- 7316
- Pages
- 707-710
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2967727
- OpenAlex
- W2071411183
- Cited by
- 525
- References
- 3
- Citations by year
- 2026: 29 · 2025: 15 · 2024: 25 · 2023: 31 · 2022: 30 · 2021: 42 · 2020: 38 · 2019: 32 · 2018: 46 · 2017: 36 · 2016: 33 · 2015: 45 · 2014: 22 · 2013: 39 · 2012: 30
- FWCI
- 21.21
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Oregon Health and Science University
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (DK56338, R01DK067636, F32DK076232, P30DK056338)
- National Center for Research Resources (S10RR023432)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
- Keywords
- hepatocyte polyploidy, multipolar mitosis, aneuploidy, genetic heterogeneity, liver regeneration, liver injury, chromosomal imbalances, genetic diversity, polyploidization
- MeSH terms
- Adaptation, Physiological, Aneuploidy, Animals, Flow Cytometry, Karyotyping, Male, Mitosis, Spindle Apparatus, Models, Genetic, Polyploidy, Genetic Variation, In Situ Hybridization, Fluorescence, Chromosome Segregation, Hepatocytes, Mice
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