Polyploidy and liver proliferation: Central role of insulin signaling
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The formation of polyploid cells is part of the developmental program in several tissues. Polyploidy is a characteristic feature of mammalian hepatocytes and it is emerging that this process is an important mechanism of restricting liver growth. We previously demonstrated that during post-natal development, binucleated tetraploid hepatocytes arise due to a failure in cytokinesis. The genesis of such binucleated tetraploid cells is the crucial step for the establishment of liver polyploidization. Our recent work identified the cellular signaling pathway controlling this process. Rats with low levels of circulating insulin exhibit reduced formation of binucleated tetraploid hepatocytes, whereas rats injected with insulin exhibit increased formation of binucleated tetraploid hepatocytes. Furthermore, modulation of Akt activity clearly controls cytokinesis failure events indicating that the PI3K-Akt pathway, downstream from the insulin signal, is central to tetraploidization process. Here, we discuss these findings in the context of how cells become polyploid during physiological or pathological growth.
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Mechanisms regulating hepatocyte ploidy include insulin signalling through the P13K-AKT pathway, which is influenced by weaning and induces formation of binucleate tetraploid hepatocytes during postnatal liver growth.
“Mechanisms regulating hepatocyte ploidy include insulin signalling through the P13K-AKT pathway, which is influenced by weaning67 and induces formation of binucleate tetraploid hepatocytes during postnatal liver growth.68,69”
From Distinct hepatocyte identities in liver homeostasis and regeneration (2023) · cites this paper as [68]
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Kim, J., Choi, H., Kim, H., Jee, Y., Noh, M., & Lee, M. (2022) · Biomolecules & Therapeutics · doi:10.4062/biomolther.2022.070 · Cited by 12 · see citing works
“The ploidy level in hepatocytes effectively reaches a plateau at maturity and hepatocytes with octaploidy (8n) appearing in significant numbers of cells during the second and third months after birth (Celton-Morizur et al., 2010).”
BackgroundInsulin-induced cell division is controlled by the adaptor Grb14 in a Chfr-dependent manner.
Perdereau, D., Cailliau, K., Browaeys-Poly, E., Lescuyer, A., Carré, N., Benhamed, F., Goenaga, D., & Burnol, A.-F. (2015) · Cellular Signalling · doi:10.1016/j.cellsig.2015.01.003 · Cited by 7
Sarkar, B., Singh, J., Yadav, M., Sharma, P., Sharma, R., Singh, S., Chandramouli, A., Mehdiratta, K., Kumar, A., Kamat, S. S., et al. (2025) · bioRxiv · doi:10.7554/elife.103817 · Cited by 6 · see citing works
Characterization of polyploidy in cancer: Current status and future perspectives
Ghosh, S., Choudhury, D., Ghosh, D., Mondal, M., Singha, D., & Malakar, P. (2024) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2024.131706 · Cited by 9 · see citing works
Inhibiting Cytokinesis in the Liver: A New Way to Reduce Tumor Development.
Desdouets, C., & Avila, M. (2018) · Gastroenterology · doi:10.1053/j.gastro.2018.03.006 · Cited by 6 · see citing works
Self-citationRajesh, R., Kotasthane, D. S., K, M., Singh, A., V, S., & Rajasekar, S. (2017) · doi:10.21276/apalm.1516 · Cited by 5
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
“Insulin has been identified as a crucial factor in the develop‐ ment of binucleate tetraploid hepatocytes (Celton-Morizur et al., 2009, 2010).”
Clerbaux, L.-A., Cordier, P., Desboeufs, N., Unger, K., Leary, P. J., Semere, G., Boege, Y., Chan, L., Desdouets, C., Lopes, M., et al. (2023) · JHEP Reports · doi:10.1016/j.jhepr.2023.100838 · Cited by 4
“21 In the liver, physiological polyploidisation starts from weaning and increases with age, 22 whereas pathological polyploidisation is observed in many chronic liver diseases.”
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Esophageal cancer detection framework based on time series information from smear images
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Using Single-Cell RNA-Seq Data to Trace Tissue Cells Responsive to Thyroid Hormones
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Basic Science of Liver Cancer Stem Cells and Hepatocarcinogenesis
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“Withmaturation, more than half of hepatocytes become binucleated and polyploid (Gupta, 2000; Baratta et al., 2009; Celton-Morizur et al., 2010).”
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“However, binucleated cells have also been detected in benign lesions, such as cervical squamous cells and liver cells [11,12].”
BackgroundPolyploidy in Liver Function, Mitochondrial Metabolism, and Cancer
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[Hepatic polyploidy: Dr Jekyll or Mr Hyde].
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Self-citationMultiple outcomes for PI3K/Akt/mTOR targeting in non-Hodgkin lymphoma
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“In contrast, studies in mice and rats revealed an important role of the PI3K/Akt pathway in the developmental tetraploidization process of liver cells [254].”
Study of Hepatocytes Polyploidization Peculiarities in Cholestatic Liver of Adult Rats
Kiparoidze, S., Karumidze, N., Bakuradze, E., Modebadze, I., Rusishvili, L., Kordzaia, D., & Dzidziguri, D. (2021) · Molecular & Cellular Biomechanics · doi:10.32604/mcb.2021.015596 · Cited by 1
“For this purpose, the liver can use endoreduplication mechanism characteristic of hepatocytes, which allows increasing the functional activity of the organ only by polyploidization without increasing the number of cells [18].”
BackgroundMarkov Chain Modeling Hepatitis B Virus Infection with Liver Microstructure
Zhong, H., Wang, J., & Wang, K. (2026) · CSIAM Transactions on Life Sciences · doi:10.4208/csiam-ls.so-2025-0029
“Since a hepatic lobule is around 1-1.4mm in width and a hepatocyte is about 20-30 µ m in diameter [16,33,40], we can estimate there are around 17-25 hepatocytes on the radius of a lobule, i.e. n ∈ { 17,18,...,25 } .”
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“In PDGF, FGF, insulin, oncostatin M and IL2 signaling pathways, the binding of signaling molecules to their receptors activates PI3K and PLC by cascade reaction [8-10,27,28].”
BackgroundHiebert, H. (2013) · doi:10.14288/1.0073817
“The nuclear volume fraction of hepatocytes can vary, as an estimated 30-40% of adult human hepatocytes are polyploid (binucleate, tetraploid, octoploid) [135].”
Background
- Authors
- Celton-Morizur, S., Merlen, G., Couton, D., & Desdouets, C.
- Corresponding author
- Desdouets, Chantal
- Venue
- Cell Cycle
- Publisher
- Informa UK Limited
- Published
- 2010-02
- Volume
- 9
- Issue
- 3
- Pages
- 460-466
- ISSN
- 1538-4101 (ISSN-L)
- 1551-4005
- OpenAlex
- W2067278779
- Cited by
- 75
- References
- 0
- Citations by year
- 2025: 5 · 2024: 1 · 2023: 6 · 2022: 4 · 2021: 6 · 2020: 4 · 2019: 7 · 2018: 5 · 2017: 4 · 2016: 4 · 2015: 8 · 2014: 6 · 2013: 4 · 2012: 4
- FWCI
- 3.13
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cell Cycle (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Association pour la Recherche sur le Cancer
- Agence Nationale de la Recherche (ANR-05)
- Institut National de la Santé et de la Recherche Médicale
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- polyploidy, liver growth, hepatocytes, tetraploidization, binucleated hepatocytes, cytokinesis failure, insulin signaling, PI3K/Akt signaling, Akt, liver development, liver regeneration
- MeSH terms
- Animals, Animals, Newborn, Humans, Insulin, Liver, Polyploidy, Signal Transduction, Hepatocytes, Cytokinesis, Mice, Rats
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