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The insulin/Akt pathway controls a specific cell division program that leads to generation of binucleated tetraploid liver cells in rodents
Open accessAbstract
The formation of polyploid cells is part of the developmental program of several tissues. During postnatal development, binucleated tetraploid cells arise in the liver, caused by failure in cytokinesis. In this report, we have shown that the initiation of cytokinesis failure events and the subsequent appearance of binucleated tetraploid cells are strictly controlled by the suckling-to-weaning transition in rodents. We found that daily light/dark rhythms and carbohydrate intake did not affect liver tetraploidy. In contrast, impairment of insulin signaling drastically reduced the formation of binucleated tetraploid cells, whereas repeated insulin injections promoted the generation of these liver cells. Furthermore, inhibition of Akt activity decreased the number of cytokinesis failure events, possibly through the mammalian target of rapamycin signaling complex 2 (mTORC2), which indicates that the PI3K/Akt pathway lies downstream of the insulin signal to regulate the tetraploidization process. To our knowledge, these results are the first demonstration in a physiological context that insulin signaling through Akt controls a specific cell division program and leads to the physiologic generation of binucleated tetraploid liver cells.
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“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 [69]
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Items 101–138 of 138
Cardiomyocyte Ploidy, Metabolic Reprogramming and Heart Repair
Elia, A., Mohsin, S., & Khan, M. (2023) · Cells · doi:10.3390/cells12121571 · Cited by 15
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“Developmentally programmed polyploidization occurs in multiple mammalian cell types (reviewed in [36]), including hepatocytes, which become polyploid following a failure of cytokinesis [37].”
BackgroundGuo, J., Krehl, K., Safraou, Y., Wallach, I., Braun, J., Meierhofer, D., Sack, I., & Berndt, N. (2024) · Heliyon · doi:10.1016/j.heliyon.2024.e39674 · Cited by 8
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“7,8 Cell polyploidization depends on downregulating the activity of cyclin-dependent kinases (CDKs) that drive G2/M phase progression (M-CDK) but maintaining the activity of CDKs responsible for S-phase entry.”
Mechanism-Based Cardiac Regeneration Strategies in Mammals
Naqvi, N., Iismaa, S., Graham, R., & Husain, A. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.747842 · Cited by 6
“For example, overexpression of cyclins can produce overt cardiomyocyte proliferation causing cardiomegaly; these hearts initially show hypercontractility but eventually deteriorate to become hypocontractile (Chaudhry et al., 2004).”
BackgroundInfluentialJaiswal, N., Chaudhari, R., & Chaudhari, B. (2020) · doi:10.1016/j.jddst.2020.101723 · Cited by 6
Allu, P. K. R., Cardamone, M. D., Gomes, A. S., Dall’Agnese, A., Cederquist, C., Pan, H., Dreyfuss, J. M., Enerbäck, S., & Kahn, C. R. (2023) · Molecular Metabolism · doi:10.1016/j.molmet.2023.101825 · Cited by 7
“It was also reported that speci fi c cell cycle program was achieved in hepatocytes by modulation of the insulin, and followed by Akt activity [48].”
BackgroundLiver physiological polyploidization: MicroRNA-122 a key regulator
Celton-Morizur, S., & Desdouets, C. (2017) · Clinics and Research in Hepatology and Gastroenterology · doi:10.1016/j.clinre.2016.07.006 · Cited by 5
Self-citationESRP2–microRNA-122 axis promotes the postnatal onset of liver polyploidization and maturation
Bangru, S., Chen, J., Baker, N., Das, D., Chembazhi, U. V., Derham, J. M., Chorghade, S., Arif, W., Alencastro, F., Duncan, A. W., et al. (2025) · Genes & Development · doi:10.1101/gad.352129.124 · Cited by 4
“…Sladky et al. 2020) and cMyc (Baena et al. 2005), cell cycle regulators such as p53 (Kurinna et al. 2013) and Rb (Mayhew et al. 2005), signaling pathways such as insulin – PI3K – AKT (Celton-Morizur et al. 2009) and Hippo – Yap (Zhang et al. 2017), and microRNAs such as miR-122 (Hsu et al. 2016).”
Hua, Q.-H., Zhang, X., Tian, R., She, Z., & Huang, Z. (2025) · Journal of Zhejiang University SCIENCE B · doi:10.1631/jzus.b2400127 · Cited by 4
“In rodents, reduced insulin signaling significantly de‐ creases the production of binucleate progenies, while repeated insulin injections promote the generation of polyploid hepatocytes (Celton-Morizur et al., 2009).”
InfluentialDutta, D., Khandelwal, N., Behera, A., Dongare, S., Bhattacharya, B., & Sukla, S. (2024) · Pharmacological Research · doi:10.1016/j.prenap.2024.100088 · Cited by 4
Inhibition of polyploidization in Pten‐deficient livers reduces steatosis
Moreno, E., Matondo, A. B., Bongiovanni, L., van de Lest, C. H. A., Molenaar, M. R., Toussaint, M. J. M., van Essen, S. C., Houweling, M., Helms, J. B., Westendorp, B., et al. (2022) · Liver International · doi:10.1111/liv.15384 · Cited by 4
Shoshani, O., Zipori, D., & Shani, N. (2015) · RNA & DISEASE · doi:10.14800/rd.780 · Cited by 4
“The PI3K/Akt pathway is a critical regulator of the transition of diploid hepatocytes to a tetraploid state after weaning ([26]), and also plays a role in epithelial-mesenchymal transition (EMT), tumor metastasis and H19 expression ([23]).”
BackgroundChanges in Hepatocyte Ploidy During Liver Regeneration
Duncan, A. W. (2015) · Elsevier eBooks · doi:10.1016/b978-0-12-420128-6.00012-9 · Cited by 3
Dheedene, W., Verhulst, S., Demuynck, L., Callewaert, B., de Haan, W., Vinckier, S., Wauwe, J. V., Vandervoort, P., Lox, M., Stroobants, M., et al. (2025) · Scientific Reports · doi:10.1038/s41598-025-05881-6 · Cited by 2
“…number of hepatocytes (at least 800 per sample) on images of liver cryosections either stained with Rhodamine-Phalloidine (R415, ThermoFisher) to mark hepatocyte cell borders and Hoechst to label nuclei or with H&E. Hepatocyte sizes were corrected for polyploidy, as previously described 80,81 .”
Darmasaputra, G., Lopes, S. M. C. D. S., Clevers, H. C., & Galli, M. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.04.13.536716 · Cited by 4
Cytoophidia safeguard binucleation of Drosophila male accessory gland cells
You, D.-D., Zhou, X.-L., Wang, Q.-Q., & Liu, J.-L. (2022) · bioRxiv · doi:10.1101/2022.09.27.509809 · Cited by 3
“Previous scientific studies show that the binucleation of hepatocytes and muscle cells occurs during the individual growth period from lactation to weaning, and the proportion of binucleated cells in stem cells gradually increases, which has been proved to be mainly determined by nutritional signals [2].”
BackgroundPolyploidy in Animal Development and Disease
Bandura, J. L., & Zielke, N. (2017) · Wiley eBooks · doi:10.1002/9781118647110.ch1 · Cited by 3
“Cytokinesis, including F-actin and RhoA localization along the cleavage site, is reconstituted by inhibition of Akt, but not by Rapamycin-mediated inhibition of mTORC1, suggesting that Akt regulates the cytokinesis program directly or indirectly through mTORC2 (Celton-Morizur et al. 2009).”
BackgroundReproductive performance: at the cross-road of genetics, technologies and environment
Vaiman, D. (2014) · Reproduction Fertility and Development · doi:10.1071/rd14316 · Cited by 3
Dietary Rhythms and MASLD-Related Hepatocellular Carcinoma
Malakmahmoudi, N., Pisu, R., Laconi, E., & Marongiu, F. (2024) · Cancers · doi:10.3390/cancers16203481 · Cited by 3
Conserved Chamber-Specific Polyploidy Maintains Heart Function in Drosophila
Chakraborty, A., Peterson, N. G., King, J. S., Gross, R., Pla, M. M., Thennavan, A., Zhou, K. C., DeLuca, S., Bursac, N., Bowles, D., et al. (2023) · bioRxiv · doi:10.1101/2023.02.10.528086 · Cited by 2
“…al., 2020; Zielke et al., 2011), which can regulate polyploidization, cell growth and cell proliferation (Bohni et al., 1999; Britton et al., 2002; Celton-Morizur et al., 2009; O’Brien et al., 2011; Saucedo et al., 2003; Shingleton et al., 2005; Shirakawa et al., 2017; Tamori and Deng, 2013;…”
BackgroundThe frequency and consequences of multipolar mitoses in undifferentiated embryonic stem cells
Pospíšilová, V., Ešner, M., Cervenkova, I., Fedr, R., Tinévez, J.-Y., Hampl, A., & Anger, M. (2019) · Journal of Applied Biomedicine · doi:10.32725/jab.2019.018 · Cited by 2
“Similar to our current results, most hepatocytes acquire polyploidy via cytokinesis failure (Celton-Morizur et al., 2009).”
ResultThe polyploid state plays a tumor suppressive role in the liver
Zhang, S.-Y., Zhou, K.-J., Luo, X.-Y., Li, L., Nguyen, L. H., Zhang, Y., Tarlow, B. D., Siegwart, D., & Zhu, H. (2017) · bioRxiv · doi:10.1101/149799 · Cited by 2
Hepatocyte Growth, Proliferation and Experimental Carcinogenesis
Ledda‐Columbano, G. M., & Columbano, A. (2010) · Molecular pathology library · doi:10.1007/978-1-4419-7107-4_54 · Cited by 1
Stereo-cell deciphers the spatial and functional heterogeneity of polyploid hepatocytes
Yang, Y., Luo, J., Cai, Y., Guo, P., Guo, Q., Wu, H., Liu, L., & Hao, S. (2026) · GigaScience · doi:10.1093/gigascience/giag023 · Cited by 1
“Polyploidization is critically regulated by the PI3K-AKT pathway [ 14 ], MAPK pathway [ 15 ], and E2F transcription factors [ 16–18 ], and knockdown of E2F8 demonstrates a decrease in polyploidy in the liver.”
Breaking the rules of cell biology: Lessons from the liver's exceptional regenerative capacity
Knouse, K. A. (2025) · Molecular Biology of the Cell · doi:10.1091/mbc.e24-06-0281 · Cited by 3
“In mice, hepatocytes become polyploid during early postnatal development around the time of weaning (Celton-Morizur et al. , 2009).”
Zhang, Y., Lu, Y., Wang, N., Hao, F., Chen, Y., Fei, X., & Wang, J. (2025) · Scientific Reports · doi:10.1038/s41598-025-90004-4 · Cited by 1
“Researchers have reported that hepatocytes are almost exclusively diploid in rodents after birth and the proportion of polyploid hepatocytes grows rapidly during weening 24 .”
Polyploidy in Liver Function, Mitochondrial Metabolism, and Cancer
Delgado, E. R., Stahl, E. C., Roy, N., Wilkinson, P. D., & Duncan, A. W. (2020) · Wiley eBooks · doi:10.1002/9781119436812.ch47 · Cited by 2
Donné, R., Saroul-Aïnama, M., Maillet, V., Celton‐Morizur, S., & Desdouets, C. (2019) · médecine/sciences · doi:10.1051/medsci/2019094 · Cited by 2
Self-citationPolyploïdie cellulaire dans le tissu hépatique : nouveau rôle de l’insuline
Celton-Morizur, S., & Desdouets, C. (2009) · médecine/sciences · doi:10.1051/medsci/2009256-7651 · Cited by 1
Self-citationTakegahara, N. (2019) · Elsevier eBooks · doi:10.1016/b978-0-12-801238-3.11163-8 · Cited by 2
Sarda, S., Apacible, A. D. C., Mahajan, R., & Dandapat, S. (2025) · International Journal of Public Research in Medicine and Health · doi:10.66328/ijprmh.2026.0201002
“Contemporary experimental data further indicate that age-dependent alterations in cyclin-dependent kinase regulation and mitotic checkpoint fidelity may predispose hepatocytes to binucleation [8,11].”
Zuccaro, M., Georgieva, D., Xu, S.-Y., Dennen, M. S., Du, Q., Chia, G., Amrane, S., Grossman, L. C., Angeles, A. D. L., Prosser, R., et al. (2025) · bioRxiv · doi:10.1101/2025.08.30.673237
“Failure of cytokinesis involves the lack of the formation of a midbody, even as two groups of chromosomes do separate from each other (Celton-Morizur et al., 2009).”
Barrull-Mascaró, R., Veltkamp, S., Boutaibi, S., van Rijnberk, L. M., Lippmann, R., & Galli, M. (2025) · bioRxiv · doi:10.1101/2025.08.04.668394
The role of somatic polyploidy in various liver pathologies in rats
Karumidze, N., & Dzidziguri, D. (2019) · Translational and Clinical Medicine - Georgian Medical Journal · doi:10.29088/tcm-gmj.2019-08
Rôle de la MAP kinase p38α au cours d'une agression aiguë du foie
Fortier, M. (2018) · theses.fr (ABES) · doi:10.70675/e84deb7azb3a0z4bdfzbe35z748fecef19af
“L’aug e tatio da s le tissu h pati ue de la o e t atio ho o ale d’i suli e au o e t du sev age o t ôle spécifiquement la genèse des hépatocytes polyploïdes (Celton-Morizur et al., 2009).”
BackgroundInfluentialRole of FXR in the adaptive response to bile acids during pregnancy
Milona, A. (2009) · doi:10.25560/4727
“Therefore, it is proposed that insulin has a role in liver growth at this point (Celton-Morizur et al, 2009).”
Background
Metadata
- Authors
- Celton-Morizur, S., Merlen, G., Couton, D., Margall-Ducos, G., & Desdouets, C.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Institut Cochin (FR)
- Corresponding author
- Desdouets, Chantal
- Venue
- Journal of Clinical Investigation
- Published
- 2009-06-15
- Volume
- 119
- Issue
- 7
- Pages
- 1880-7
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC2701880
- OpenAlex
- W2108877086
- Cited by
- 145
- References
- 0
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 6 · 2023: 8 · 2022: 14 · 2021: 13 · 2020: 13 · 2019: 15 · 2018: 9 · 2017: 10 · 2016: 6 · 2015: 10 · 2014: 5 · 2013: 10 · 2012: 8
- FWCI
- 4.11
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- 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 › Molecular Biology › Metabolism, Diabetes, and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- insulin signaling, Akt, tetraploidy, cytokinesis failure, polyploidy, mTORC2, PI3K/Akt signaling, liver development, postnatal development, rodents
- MeSH terms
- Animals, Cell Division, Dietary Carbohydrates, Insulin, Mice, Obese, Polyploidy, Signal Transduction, Rats, Wistar, Phosphatidylinositol 3-Kinases, Hepatocytes, Proto-Oncogene Proteins c-akt, Mice, Rats
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