The Polyploid State Restricts Hepatocyte Proliferation and Liver Regeneration in Mice
Open accessAbstract
The liver contains a mixture of hepatocytes with diploid or polyploid (tetraploid, octaploid, etc.) nuclear content. Polyploid hepatocytes are commonly found in adult mammals, representing ~90% of the entire hepatic pool in rodents. The cellular and molecular mechanisms that regulate polyploidization have been well characterized; however, it is unclear whether diploid and polyploid hepatocytes function similarly in multiple contexts. Answering this question has been challenging because proliferating hepatocytes can increase or decrease ploidy, and animal models with healthy diploid‐only livers have not been available. Mice lacking E2f7 and E2f8 in the liver (liver‐specific E2f7/E2f8 knockout; LKO) were recently reported to have a polyploidization defect, but were otherwise healthy. Herein, livers from LKO mice were rigorously characterized, demonstrating a 20‐fold increase in diploid hepatocytes and maintenance of the diploid state even after extensive proliferation. Livers from LKO mice maintained normal function, but became highly tumorigenic when challenged with tumor‐promoting stimuli, suggesting that tumors in LKO mice were driven, at least in part, by diploid hepatocytes capable of rapid proliferation. Indeed, hepatocytes from LKO mice proliferate faster and out‐compete control hepatocytes, especially in competitive repopulation studies. In addition, diploid or polyploid hepatocytes from wild‐type (WT) mice were examined to eliminate potentially confounding effects associated with E2f7/E2f8 deficiency. WT diploid cells also showed a proliferative advantage, entering and progressing through the cell cycle faster than polyploid cells, both in vitro and during liver regeneration (LR). Diploid and polyploid hepatocytes responded similarly to hepatic mitogens, indicating that proliferation kinetics are unrelated to differential response to growth stimuli. Conclusion: Diploid hepatocytes proliferate faster than polyploids, suggesting that the polyploid state functions as a growth suppressor to restrict proliferation by the majority of hepatocytes.
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Livers enriched for diploid hepatocytes showed a regeneration advantage over normal adult mouse livers with ∼90% polyploid hepatocytes.
“Livers enriched for diploid hepatocytes showed a regeneration advantage over normal adult mouse livers with ∼90% polyploid hepatocytes38”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [38]
The Introduction says adult mouse hepatocytes are about 90% polyploid, and the Discussion reports a modest proliferation advantage for diploid-enriched LKO hepatocytes after partial hepatectomy. But the Results say liver-mass recovery was nearly equivalent in LKO and control mice. The stronger advantage was in competitive repopulation, so the claim overstates the evidence for better regeneration of intact diploid-enriched livers. (LLM, conf=0.87)
Experimental — accuracy not yet measuredPolyploidization is implicated in maintaining genomic stability, buffering metabolic demands, and enhancing stress resistance.
“Importantly, polyploidization is not only a form of cellular growth but is also implicated in maintaining genomic stability, buffering metabolic demands, and enhancing stress resistance.”
From Liver regeneration after partial hepatectomy: Triggers and mechanisms (2025) · cites this paper as [80]
The Discussion (page not provided) says extra chromosome copies in polyploid hepatocytes buffer against tumor-suppressor inactivation, supporting a narrower form of genomic protection. It does not say polyploidization buffers metabolic demands or enhances stress resistance. (LLM, conf=0.87)
Experimental — accuracy not yet measuredWhile diploid hepatocytes dominate the early proliferative response following major hepatectomy, polyploid hepatocytes contribute to regeneration through selective division and hypertrophy, particularly when proliferation is delayed or impaired.
“While diploid hepatocytes have been shown to dominate the early proliferative response following major hepatectomy, polyploid hepatocytes contribute to regeneration through selective division and hypertrophy, particularly under conditions where proliferation is delayed or impaired[80,81].”
From Liver regeneration after partial hepatectomy: Triggers and mechanisms (2025) · cites this paper as [80]
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Experimental — accuracy not yet measuredE2F7 and E2F8 are cell cycle factors expressed at low levels in adult livers but at high levels during the first 7 weeks after birth in mice; they are also responsible for postnatal polyploidisation.
“E2F7 and E2F8 are cell cycle factors expressed at low levels in adult livers but at high levels during the first 7 weeks after birth in mice; they are also responsible for postnatal polyploidisation.38,70”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [38]
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Cites
Michalopoulos, G. K. (2007) · Journal of Cellular Physiology · doi:10.1002/jcp.21172 · Cited by 1,384 · see citing works
Liver Cell Polyploidization: A Pivotal Role for Binuclear Hepatocytes
Guidotti, J.-E., Brégerie, O., Robert, A., Debey, P., Brechot, C., & Desdouets, C. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m300982200 · Cited by 315 · see citing works
The Polyploid State Plays a Tumor-Suppressive Role in the Liver
Zhang, S., Zhou, K., Luo, X., Li, L., Tu, H.-C., Sehgal, A., Nguyen, L. H., Zhang, Y., Gopal, P., Tarlow, B. D., et al. (2018) · Developmental Cell · doi:10.1016/j.devcel.2018.01.010 · Cited by 180 · cited 8× · see citing works
“, differentiation genes such as Albumin, forkhead box protein 3, and hepatocyte nuclear factor 4 alpha; cytochrome P450 family members; and cell-cycle genes).(10,16) To assess liver function following chronic injury, we maintained mice on a high-fat diet for 8 weeks.”
InfluentialE2F8 is essential for polyploidization in mammalian cells
Pandit, S. K., Westendorp, B., Nantasanti, S., van Liere, E., Tooten, P. C. J., Cornelissen, P. W. A., Toussaint, M. J. M., Lamers, W. H., & de Bruin, A. (2012) · Nature Cell Biology · doi:10.1038/ncb2585 · Cited by 168 · cited 9× · see citing works
“Acknowledgment: We thank Gustavo Leone (The Ohio State University) and Alain deBruin (Utrecht University) for sharing liver-specific E2f 7/E2f 8 knockout mice.”
InfluentialCanonical and atypical E2Fs regulate the mammalian endocycle
Chen, H.-Z., Ouseph, M. M., Li, J., Pécot, T., Chokshi, V., Kent, L., Bae, S., Byrne, M., Duran, C., Comstock, G., et al. (2012) · Nature Cell Biology · doi:10.1038/ncb2595 · Cited by 161 · see citing works
E2f8 mediates tumor suppression in postnatal liver development
Kent, L. N., Rakijas, J. B., Pandit, S. K., Westendorp, B., Chen, H.-Z., Huntington, J. T., Tang, X., Bae, S., Srivastava, A., Senapati, S., et al. (2016) · Journal of Clinical Investigation · doi:10.1172/jci85506 · Cited by 95 · see citing works
Flagged first, then by citations
Research works printed but not linked: 38
- [1]Gentric G, Desdouets C. Polyploidization in liver tissue. Am J Pathol 2014; 184: 322– 331. 24140012
- [2]Duncan AW. Aneuploidy, polyploidy and ploidy reversal in the liver. Semin Cell Dev Biol 2013; 24: 347– 356. 23333793
- [3]Pandit SK, Westendorp B, de Bruin A. Physiological significance of polyploidization in mammalian cells. Trends Cell Biol 2013; 23: 556– 566. 23849927
- [4]Duncan AW, Hanlon Newell AE, Smith L, Wilson EM, Olson SB, Thayer MJ, Strom SC, Frequent aneuploidy among normal human hepatocytes. Gastroenterology 2012; 142: 25– 28. 22057114 PMC3244538
- [5]Duncan AW, Taylor MH, Hickey RD, Hanlon Newell AE, Lenzi ML, Olson SB, Finegold MJ, The ploidy conveyor of mature hepatocytes as a source of genetic variation. Nature 2010; 467: 707– 710. 20861837 PMC2967727
- [7]Margall-Ducos G, Celton-Morizur S, Couton D, Bregerie O, Desdouets C. Liver tetraploidization is controlled by a new process of incomplete cytokinesis. J Cell Sci 2007; 120: 3633– 3639. 17895361
- [8]Hsu SH, Delgado ER, Otero PA, Teng KY, Kutay H, Meehan KM, Moroney JB, MicroRNA-122 regulates polyploidization in the murine liver. Hepatology 2016; 64: 599– 615. 27016325 PMC4956491
- [9]Knouse KA, Wu J, Whittaker CA, Amon A. Single cell sequencing reveals low levels of aneuploidy across mammalian tissues. Proc Natl Acad Sci U S A 2014; 111: 13409– 13414. 25197050 PMC4169915
- [10]Xanthoulis A, Tiniakos DG. E2F transcription factors and digestive system malignancies: how much do we know? World J Gastroenterol 2013; 19: 3189– 3198. 23745020 PMC3671070
- [13]Conner EA, Lemmer ER, Sanchez A, Factor VM, Thorgeirsson SS. E2F1 blocks and c-Myc accelerates hepatic ploidy in transgenic mouse models. Biochem Biophys Res Commun 2003; 302: 114– 120. 12593856
- [14]Azuma H, Paulk N, Ranade A, Dorrell C, Al-Dhalimy M, Ellis E, Strom S, Robust expansion of human hepatocytes in Fah−/−/Rag2−/−/Il2rg−/− mice. Nat Biotechnol 2007; 25: 903– 910. 17664939 PMC3404624
- [15]Wilson EM, Bial J, Tarlow B, Bial G, Jensen B, Greiner DL, Brehm MA, Extensive double humanization of both liver and hematopoiesis in FRGN mice. Stem Cell Res 2014; 13: 404– 412. 25310256 PMC7275629
- [16]Overturf K, Al-Dhalimy M, Tanguay R, Brantly M, Ou CN, Finegold M, Grompe M. Hepatocytes corrected by gene therapy are selected in vivo in a murine model of hereditary tyrosinaemia type I. Nat Genet 1996; 12: 266– 273. 8589717
- [18]Ganem NJ, Storchova Z, Pellman D. Tetraploidy, aneuploidy and cancer. Curr Opin Genet Dev 2007; 17: 157– 162. 17324569
- [19]Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011; 144: 646– 674. 21376230
- [20]Zhang S, Li L, Kendrick SL, Gerard RD, Zhu H. TALEN-mediated somatic mutagenesis in murine models of cancer. Cancer Res 2014; 74: 5311– 5321. 25070752 PMC4167541
- [21]Aydinlik H, Nguyen TD, Moennikes O, Buchmann A, Schwarz M. Selective pressure during tumor promotion by phenobarbital leads to clonal outgrowth of beta-catenin-mutated mouse liver tumors. Oncogene 2001; 20: 7812– 7816. 11753661
- [22]Loeppen S, Schneider D, Gaunitz F, Gebhardt R, Kurek R, Buchmann A, Schwarz M. Overexpression of glutamine synthetase is associated with beta-catenin-mutations in mouse liver tumors during promotion of hepatocarcinogenesis by phenobarbital. Cancer Res 2002; 62: 5685– 5688. 12384525
- [23]Moennikes O, Buchmann A, Romualdi A, Ott T, Werringloer J, Willecke K, Schwarz M. Lack of phenobarbital-mediated promotion of hepatocarcinogenesis in connexin32-null mice. Cancer Res 2000; 60: 5087– 5091. 11016633
- [24]Schmid A, Rignall B, Pichler BJ, Schwarz M. Quantitative analysis of the growth kinetics of chemically induced mouse liver tumors by magnetic resonance imaging. Toxicol Sci 2012; 126: 52– 59. 22273797
- [25]Honkakoski P, Zelko I, Sueyoshi T, Negishi M. The nuclear orphan receptor CAR-retinoid X receptor heterodimer activates the phenobarbital-responsive enhancer module of the CYP2B gene. Mol Cell Biol 1998; 18: 5652– 5658. 9742082 PMC109151
- [26]Li L, Bao X, Zhang QY, Negishi M, Ding X. Role of CYP2B in Phenobarbital-Induced Hepatocyte Proliferation in Mice. Drug Metab Dispos 2017; 45: 977– 981. 28546505 PMC5518717
- [27]Shirakami Y, Gottesman ME, Blaner WS. Diethylnitrosamine-induced hepatocarcinogenesis is suppressed in lecithin:retinol acyltransferase-deficient mice primarily through retinoid actions immediately after carcinogen administration. Carcinogenesis 2012; 33: 268– 274. 22116467 PMC3271263
- [28]Bakiri L, Wagner EF. Mouse models for liver cancer. Mol Oncol 2013; 7: 206– 223. 23428636 PMC5528415
- [29]Cieply B, Zeng G, Proverbs-Singh T, Geller DA, Monga SP. Unique phenotype of hepatocellular cancers with exon-3 mutations in beta-catenin gene. Hepatology 2009; 49: 821– 831. 19101982 PMC2657345
- [32]Michalopoulos GK, DeFrances MC. Liver regeneration. Science 1997; 276: 60– 66. 9082986
- [33]Higgins G, Anderson GM. Experimental pathology of the liver. Restoration of the liver of the white rat following partial surgical removal. Arch Pathol 1931; 12: 186– 202.
- [34]Miyaoka Y, Ebato K, Kato H, Arakawa S, Shimizu S, Miyajima A. Hypertrophy and unconventional cell division of hepatocytes underlie liver regeneration. Curr Biol 2012; 22: 1166– 1175. 22658593
- [35]Michalopoulos GK. Liver regeneration after partial hepatectomy: critical analysis of mechanistic dilemmas. Am J Pathol 2010; 176: 2– 13. 20019184 PMC2797862
- [36]Kreutz C, MacNelly S, Follo M, Waldin A, Binninger-Lacour P, Timmer J, Bartolome-Rodriguez MM. Hepatocyte Ploidy Is a Diversity Factor for Liver Homeostasis. Front Physiol 2017; 8: 862. 29163206 PMC5671579
- [37]Bowen WC, Michalopoulos AW, Orr A, Ding MQ, Stolz DB, Michalopoulos GK. Development of a chemically defined medium and discovery of new mitogenic growth factors for mouse hepatocytes: mitogenic effects of FGF1/2 and PDGF. PLoS One 2014; 9: e95487. 24743506 PMC3990636
- [38]Lu P, Prost S, Caldwell H, Tugwood JD, Betton GR, Harrison DJ. Microarray analysis of gene expression of mouse hepatocytes of different ploidy. Mamm Genome 2007; 18: 617– 626. 17726633
- [39]Johnson DG. The paradox of E2F1: oncogene and tumor suppressor gene. Mol Carcinog 2000; 27: 151– 157. 10708476
- [40]Anti M, Marra G, Rapaccini GL, Rumi C, Bussa S, Fadda G, Vecchio FM, DNA ploidy pattern in human chronic liver diseases and hepatic nodular lesions. Flow cytometric analysis on echo-guided needle liver biopsy. Cancer 1994; 73: 281– 288. 8293389
- [41]Rua S, Comino A, Fruttero A, Torchio P, Bouzari H, Taraglio S, Torchio B, Flow cytometric DNA analysis of cirrhotic liver cells in patients with hepatocellular carcinoma can provide a new prognostic factor. Cancer 1996; 78: 1195– 1202. 8826940
- [42]Saeter G, Schwarze PE, Nesland JM, Seglen PO. Diploid nature of hepatocellular tumours developing from transplanted preneoplastic liver cells. Br J Cancer 1989; 59: 198– 205. 2930686 PMC2247004
- [43]Gentric G, Maillet V, Paradis V, Couton D, L’Hermitte A, Panasyuk G, Fromenty B, Oxidative stress promotes pathologic polyploidization in nonalcoholic fatty liver disease. J Clin Invest 2015; 125: 981– 992. 25621497 PMC4362240
- [44]Sigal SH, Rajvanshi P, Gorla GR, Sokhi RP, Saxena R, Gebhard DR Jr., Reid M, Partial hepatectomy-induced polyploidy attenuates hepatocyte replication and activates cell aging events. Am J Physiol 1999; 276: G1260– 1272. 10330018
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Self-citation
- Authors
- Wilkinson, P. D., Delgado, E. R., Alencastro, F., Leek, M. P., Roy, N., Weirich, M. P., Stahl, E. C., Otero, P. A., Chen, M. I., Brown, W. K., & Duncan, A. W.
- Affiliations
- University of Pittsburgh (US)
- Corresponding author
- Duncan, Andrew W.
- ORCID
- Venue
- Hepatology
- Published
- 2019-02-15
- Volume
- 69
- Issue
- 3
- Pages
- 1242-1258
- ISSN
- 0270-9139 (ISSN-L)
- 1527-3350
- PMC
- PMC6532408
- OpenAlex
- W2892870770
- Cited by
- 135
- References
- 6
- Citations by year
- 2026: 14 · 2025: 17 · 2024: 14 · 2023: 12 · 2022: 18 · 2021: 24 · 2020: 18 · 2019: 16 · 2018: 2
- FWCI
- 9.40
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Commonwealth of Pennsylvania
- University of Pittsburgh
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (F31DK112633, R01DK103645)
- National Institute of Biomedical Imaging and Bioengineering (T32EB001026)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Surgery › Organ Transplantation Techniques and Outcomes
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- polyploidy, hepatocyte proliferation, liver regeneration, competitive repopulation, cell cycle kinetics, growth inhibition
- MeSH terms
- Animals, Female, Liver Regeneration, Male, Mice, Inbred C57BL, Polyploidy, Hepatocytes, Cell Proliferation, Mice
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