The origins and functions of hepatic polyploidy
Open accessAbstract
Polyploid cells contain more than two homologous sets of chromosomes. The original observations of liver polyploidy date back to the 1940s, but functional roles for polyploid cells are still unclear. Liver polyploidy may influence regeneration, stress response, and cancer, although little evidence has established direct causal links between polyploidy and these biological phenotypes. In this review, we will introduce broad concepts about polyploidy including its distribution in nature and how polyploids form in normal and pathological situations. Then we will examine recent discoveries that have begun to clarify functionality and disease relevance of liver polyploidy. Finally, we will discuss implications and future directions of research about polyploidy in the liver.
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Expression of E2f7 and E2f8 is induced at weaning when the liver switches from diploid to polyploid.
“Expression of E2f7 and E2f8 is induced at the time of weaning when the tissue switches from initially containing diploid hepatocytes to becoming mostly polyploid (4, 9, 10).”
From Wnt signaling regulates hepatocyte cell division by a transcriptional repressor cascade (2022) · cites this paper as [10]
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Polyploidy in liver development, homeostasis and disease
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“Both single and multi-nucleated polyploid cells can occur depending on the poly-ploidization pathway [(cid:65)1,184,22(cid:72),230].”
BackgroundCommunal living: the role of polyploidy and syncytia in tissue biology
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The “Golden Age” of Behavior Genetics?
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“Expression of E2f7 and E2f8 is induced at the time of weaning when the tissue switches from initially containing diploid hepatocytes to becoming mostly polyploid (4, 9, 10).”
BackgroundPek, N. M. Q., Liu, K. J., Nichane, M., & Ang, L. T. (2020) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2020.09.016 · Cited by 25 · see citing works
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“Since the liver is a highly polyploid organ (Zhang et al., 2019), and polyploid cells are bigger than diploid cells, we sorted the isolated hepatocytes based on viability and on ploidy before size measurements were made in order to eliminate the confounding effect of ploidy on size (Figure 1C, Supplementary Figure S1A…”
MethodSelf-citationp53 regulates diverse tissue-specific outcomes to endogenous DNA damage in mice
Hill, R. J., Bona, N., Smink, J., Webb, H. K., Crisp, A., Garaycoechea, J. I., & Crossan, G. P. (2024) · Nature Communications · doi:10.1038/s41467-024-46844-1 · Cited by 18 · see citing works
Transcriptome signature changes in the liver of a migratory passerine
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Opposing roles of HDAC6 in liver regeneration and hepatocarcinogenesis
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Ssu72 Dual-Specific Protein Phosphatase: From Gene to Diseases
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“Such cells are susceptible to aneuploidy and/or apoptotic cell death in response to injury or stress signals [83,84].”
BackgroundThe Controversial Role of Polyploidy in Hepatocellular Carcinoma
Wang, N., Hao, F., Shi, Y., & Wang, J.-Q. (2021) · OncoTargets and Therapy · doi:10.2147/ott.s340435 · Cited by 11 · see citing works
“However, the existence of hepatocyte fusion in the liver is still controversial due to the possible formation of artifacts of extracellular vesicles that interfere with the observation of cell ploidy, which needs further investigation.(21)”
BackgroundAl-Naggar, I. M. A., Antony, M., Baker, D., Wang, L., Godoy, L. D. C., Kuo, C.-L., Fraser, M., Smith, P. P., Xu, M., & Kuchel, G. (2024) · Aging Cell · doi:10.1111/acel.14399 · Cited by 10 · see citing works
“In mammals, polyploid cells can be generated by 3 noncanonical cell cycles in vivo (Zhang et al., 2019 ).”
Polyploid tubular cells: a shortcut to stress adaptation
Chiara, L. D., Lazzeri, E., & Romagnani, P. (2024) · Kidney International · doi:10.1016/j.kint.2023.10.036 · Cited by 10 · see citing works
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Kim, J., Yang, I. S., Kim, H., Yoon, J.-Y., Han, Y., Seong, J. K., & Lee, M. (2021) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00309.2021 · Cited by 7 · see citing works
Hu, C., Hsiao, Z. H., Yin, L., & Yu, X. (2023) · Toxicological Sciences · doi:10.1093/toxsci/kfad005 · Cited by 6 · see citing works
Major genomic mutations driving hepatocellular carcinoma
Chen, R., Lin, M.-B., & Gao, D.-M. (2023) · Genome Instability & Disease · doi:10.1007/s42764-023-00103-7 · Cited by 6 · see citing works
“As polyploid is usually associated with hemostasis and normal functions of healthy liver, polyploid is now generally characterized as a gatekeeper of tumorigenesis in liver (Zhang et al., 2019).”
BackgroundEpithelial–mesenchymal transition: an organizing principle of mammalian regeneration
Bedelbaeva, K., Cameron, B., Latella, J., Aslanukov, A., Gourevitch, D., Davuluri, R. V., & Heber‐Katz, E. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1101480 · Cited by 6 · see citing works
Liver Regeneration: Polyploidy and Cellular Senescence as Potential Regulators
Jalise, S. Z., Habibi, S., Khosrowpour, Z., Piryaei, A., Hosseinzadeh, F., Nigjeh, M. N., & Fath‐Bayati, L. (2025) · Stem Cell Reviews and Reports · doi:10.1007/s12015-025-11001-8 · Cited by 5 · see citing works
“Within the framework of liver development and the maintenance of homeostasis, this condition assumes a pivotal and highly influential role [ 7].”
Deep-Learning-Based Hepatic Ploidy Quantification Using H&E Histopathology Images
Wen, Z., Lin, Y.-H., Wang, S.-D., Fujiwara, N., Rong, R., Jin, K. W., Yang, D.-H. M., Yao, B., Yang, S., Wang, T., et al. (2023) · Genes · doi:10.3390/genes14040921 · Cited by 5 · see citing works
Self-citationZhang, Y., Wang, N., Hao, F., Chen, Y., Fei, X., & Wang, J. (2023) · The FASEB Journal · doi:10.1096/fj.202301219r · Cited by 5 · see citing works
Hua, Q., Zhang, X.-C., Tian, R.-F., She, Z.-G., & Huang, Z. (2025) · Journal of Zhejiang University SCIENCE B · doi:10.1631/jzus.b2400127 · Cited by 4 · see citing works
“Indeed, paradoxically, polyploidy has been shown to both promote and sup‐ press tumorigenesis (Ganem et al., 2007; Zhang et al., 2018b, 2019; Bou-Nader et al., 2020).”
Hicks, J. A., Pike, B., & Liu, H. (2022) · Frontiers in Physiology · doi:10.3389/fphys.2022.1020870 · Cited by 4 · see citing works
“Polyploidization of hepatocytes has also been linked to the metabolic capacity of the liver (Zhang et al., 2019).”
BackgroundAssessment of Hepatocyte Ploidy by Flow Cytometry
Jin, Y., Anbarchian, T., & Nusse, R. (2022) · Methods in molecular biology · doi:10.1007/978-1-0716-2557-6_12 · Cited by 3 · see citing works
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“Accumulating evidence has been reported that polyploid exerts pivotal bio-functions in the liver, including undertaking complex and tremendous physiological processes, promoting tissue regeneration after chronic liver injury, and buffering chromosome aberration referring to tumorigenesis [9, 10].”
BackgroundMature rat hepatocyte dedifferentiation into long lived proliferating hepatic progenitor cells
Grigoriev, A. M., Kholodenko, I. V., Lupatov, A. Y., Kholodenko, R. V., Кирсанова, Л. А., Basok, Y. B., Yarygin, K. N., & Sevastianov, V. I. (2021) · Russian Journal of Transplantology and Artificial Organs · doi:10.15825/1995-1191-2021-3-148-161 · Cited by 1 · see citing works
Dietary Fat Quality in Normolipidic Diets Affects Hepatocyte’s Nuclear Phenotypes
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Areshidze, D. A., Kirillov, Y. A., Андреевна, М. Л., Kozlova, M., Chernov, I. A., & Shtemplevskaya, E. (2021) · Caryologia · doi:10.36253/caryologia-1122
“In addition, it was found that ploidy of hepatocytes increases with aging, after hepatectomy, under the influence of a number of unfavorable factors, but at the same time ploidy decreases, for example, in hepatocellular carcinomas (Duncan, 2013; Zhang et al., 2019; Donne et al., 2020).”
BackgroundPolyviana, O. A., Stetsuk, E. V., Shepitko, V., Vilkhova, O., Boruta, N., Rud, M., Pelypenko, L. B., Lysachenko, O. D., Voloshyna, O. V., Dvornyk, I., et al. (2025) · Reports of Morphology · doi:10.31393/morphology-journal-2025-31(1)-07
“The above indicates the potential benefit of this flavonoid in the treatment of various liver diseases, in particular non-alcoholic fatty liver disease, chronic hepatitis of various etiologies and drug-associated liver diseases [9, 10, 13, 35].”
Polyvyana, O. A., Stetsuk, Y. V., Shepitko, V. I., Boruta, N. V., Vilkhova, O. V., Pelypenko, L. B., & Lysachenko, О. D. (2025) · Bulletin of Problems Biology and Medicine · doi:10.29254/2077-4214-2025-1-176-452-460
张一帆, Lu, Y., Yang, Y., Luo, X., Wang, N., Hao, F., Li, W., Chen, Y., & Wang, J. (2026) · Frontiers in Oncology · doi:10.3389/fonc.2026.1906245
“This discovery is also consistent with an intensive study by Zhu et al., which documented the genetic and cellular mechanisms of liver regeneration concerning hepatocyte composition (27, 28).”
- Authors
- Zhang, S., Lin, Y.-H., Tarlow, B., & Zhu, H.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Zhu, Hao
- Venue
- Cell Cycle
- Publisher
- Informa UK Limited
- Published
- 2019-05-26
- Volume
- 18
- Issue
- 12
- Pages
- 1302-1315
- ISSN
- 1538-4101 (ISSN-L)
- 1551-4005
- OpenAlex
- W2946183559
- Cited by
- 38
- References
- 124
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 3 · 2023: 7 · 2022: 8 · 2021: 10 · 2020: 5
- FWCI
- 0.75
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cell Cycle (publishedVersion)
- Funders
- National Institutes of Health (R01CA190525)
- CPRIT (RP180268)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Keywords
- polyploidy, liver, polyploid cells, liver regeneration, stress response, liver cancer
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