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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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Hepatoprotective Effect of MMP-19 Deficiency in a Mouse Model of Chronic Liver Fibrosis
Jiroušková, M., Zbodakova, O., Gregor, M., Chalupský, K., Sarnová, L., Hajdůch, M., Ehrmann, J., Jirkovská, M., & Sedláček, R. (2012) · PLoS ONE · doi:10.1371/journal.pone.0046271 · Cited by 33
“to reduce numbers of binucleated cells [49].”
IER2-induced senescence drives melanoma invasion through osteopontin
Kyjacová, L., Saup, R., Rönsch, K., Wallbaum, S., Dukowic‐Schulze, S., Foss, A., Scherer, S. D., Rothley, M., Neeb, A., Grau, N., et al. (2021) · Oncogene · doi:10.1038/s41388-021-02027-6 · Cited by 38
“In this regard, we note that the AKT pathway, which we show is activated by IER2, is involved in context-dependent cytokinesis failure [86].”
BackgroundPatel, O. P. S., Arun, A., Singh, P., Saini, D., Karade, S. S., Chourasia, M. K., Konwar, R., & Yadav, P. (2019) · European journal of medicinal chemistry · doi:10.1016/j.ejmech.2019.02.003 · Cited by 32
Circadian clock regulates hepatic polyploidy by modulating Mkp1-Erk1/2 signaling pathway
Chao, H., Doi, M., Fustin, J., Chen, H., Murase, K., Maeda, Y., Hayashi, H., Tanaka, R., Sugawa, M., Mizukuchi, N., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-02207-7 · Cited by 35
Liver repopulation and regeneration
Duncan, A. W., & Soto–Gutiérrez, A. (2013) · Current Opinion in Organ Transplantation · doi:10.1097/mot.0b013e32835f07e2 · Cited by 29
“The primary mechanism for polyploidization involves failed cytokinesis and is related to alterations in insulin/AKT signaling [4,7,8].”
BackgroundDistinct hepatocyte identities in liver homeostasis and regeneration
Chen, F., Schönberger, K., & Tchorz, J. S. (2023) · JHEP Reports · doi:10.1016/j.jhepr.2023.100779 · Cited by 30
Moreno-Marín, N., Merino, J. M., Alvarez, A. M., Patel, D., Takahashi, S., González‐Sancho, J. M., Gandolfo, P., Rios, R. M., Múñoz, A., Gonzalez, F. J., et al. (2018) · iScience · doi:10.1016/j.isci.2018.05.006 · Cited by 37
LKB1 as a Gatekeeper of Hepatocyte Proliferation and Genomic Integrity during Liver Regeneration
Maillet, V., Boussetta, N., Leclerc, J., Fauveau, V., Foretz, M., Viollet, B., Couty, J., Celton‐Morizur, S., Perret, C., & Desdouets, C. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.01.086 · Cited by 33
“In rodent livers, hepatocyte polyploidization begins during weaning (Celton-Morizur et al., 2009).”
BackgroundSelf-citationKhalil, A., Parker, M., Mpanga, R., Cevik, S. E., Reimonn, C. A., & Suvorov, A. (2017) · Journal of the Endocrine Society · doi:10.1210/js.2016-1011 · Cited by 27
“Cytokinesis failure was mTORC1-independent, revealing that Akt controls the cytokinesis program and consequent generation of binuclear tetraploid hepatocytes directly or through mTORC2 [86].”
BackgroundDifferential Roles for Diploid and Polyploid Hepatocytes in Acute and Chronic Liver Injury
Wilkinson, P. D., & Duncan, A. W. (2020) · Seminars in Liver Disease · doi:10.1055/s-0040-1719175 · Cited by 31
DNA damage signaling and polyploid macrophages in chronic inflammation
Horn, V., & Triantafyllopoulou, A. (2017) · Current Opinion in Immunology · doi:10.1016/j.coi.2017.11.002 · Cited by 25
PIDD1 in cell cycle control, sterile inflammation and cell death
Weiler, E. S., Szabo, T., Garcia-Carpio, I., & Villunger, A. (2022) · Biochemical Society Transactions · doi:10.1042/bst20211186 · Cited by 23
Hepatocyte Polyploidy: Driver or Gatekeeper of Chronic Liver Diseases
Donné, R., Sangouard, F., Celton‐Morizur, S., & Desdouets, C. (2021) · Cancers · doi:10.3390/cancers13205151 · Cited by 28
“The inhibition of PI3K/Akt phosphorylation prevents cytokinesis failure; cytokinesis is thus completed, and this event is followed by actin cytoskeleton polarization, cytoskeleton reorganization, and RhoA recruitment to the equatorial cortex [59,60].”
BackgroundSelf-citationGirdin locates in centrosome and midbody and plays an important role in cell division
Mao, J., Jiang, P., Cui, S.-P., Ren, Y.-L., Zhao, J., Yin, X.-H., Enomoto, A., Liu, H.-J., Hou, L., Takahashi, M., et al. (2012) · Cancer Science · doi:10.1111/j.1349-7006.2012.02378.x · Cited by 23
Centriole signaling restricts hepatocyte ploidy to maintain liver integrityPreprint
Sladky, V. C., Akbari, H., Tapias-Gomez, D., Evans, L. T., Drown, C. G., Strong, M. A., LoMastro, G. M., Larman, T., & Holland, A. J. (2022) · Genes & Development · doi:10.1101/gad.349727.122 · Cited by 24
“Hepatocyte polyploidization is a tightly regulated process initiated by insulin signaling, miR122, and E2F family members (Celton-Morizur et al. 2009; Chen et al. 2012; Pandit et al. 2012; Hsu et al. 2016).”
Implications of Polyploidy and Ploidy Alterations in Hepatocytes in Liver Injuries and Cancers
Matsumoto, T. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23169409 · Cited by 29
“In addition, insulin signaling, which can be enhanced by the suckling-to-weaning transition, induces cytokinesis failure in hepatocytes via activation of the downstream PI3K/Akt pathway in rats and mice [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
A structural basis for cellular senescence
Aranda‐Anzaldo, A. (2009) · Aging · doi:10.18632/aging.100074 · Cited by 17
“This important result ties in with recent evidence in vivo that the insulin/Akt pathway directly or indirectly through TORC2, is involved in the process that leads to generation of polyploid hepatocytes in rodents [79], suggesting that growth and aging may share a common molecular mechanism [83].”
BackgroundResultPatterson, M., & Swift, S. K. (2019) · Stem Cells and Development · doi:10.1089/scd.2019.0193 · Cited by 20
Fortier, M., Cadoux, M., Boussetta, N., Pham, S., Donné, R., Couty, J., Desdouets, C., & Celton‐Morizur, S. (2019) · Scientific Reports · doi:10.1038/s41598-019-51175-z · Cited by 19
Self-citationThe contributions of mesoderm-derived cells in liver development
Li, Y., Li, L., Lamaoqiezhong, Wang, X., Wang, W., Wang, Y., & Xu, C. (2018) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2018.09.003 · Cited by 35
Puzzonia, M. D. S., Cozzolino, A. M., Grassi, G., Bisceglia, F., Strippoli, R., Guarguaglini, G., Citarella, F., Sacchetti, B., Tripodi, M., Marchetti, A., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0167158 · Cited by 22
Pathological polyploidy in liver disease
Hsu, S., & Duncan, A. W. (2015) · Hepatology · doi:10.1002/hep.27908 · Cited by 20
“Notably, Chantal Desdouets’ group previously demonstrated a critical role for insulin in the generation of binucleate polyploid hepatocytes in rats.(3) Motivated by these early findings, Gentric et al.”
BackgroundTaniguchi, K., Kokuryo, A., Imano, T., Minami, R., Nakagoshi, H., & Adachi-Yamada, T. (2012) · doi:10.4172/2329-6577.1000e101 · Cited by 19
“In rat hepatocytes, the proportion of binucleate cells increase in the transition from suckling to weaning, and the rate of binucleation is controlled by nutrient signaling [1].”
BackgroundRat liver epigenome programing by perinatal exposure to 2,2',4'4'-tetrabromodiphenyl ether.
Suvorov, A., Naumov, V., Shtratnikova, V., Logacheva, M., Shershebnev, A., Wu, H., Gerasimov, E., Zheludkevich, A., Pilsner, J., & Sergeyev, O. (2019) · Epigenomics · doi:10.2217/epi-2019-0315 · Cited by 17
Wigger, L., Casals‐Casas, C., Baruchet, M., Trang, B. K., Pradervand, S., Naldi, A., & Desvergne, B. (2019) · PLoS ONE · doi:10.1371/journal.pone.0220894 · Cited by 19
“This effect could involve the insulin-signaling pathway, which is sitting at the cross-road of many metabolic pathways, and contributes to the formation of binucleated tetraploid liver cells through the PI3K/Akt pathway [43].”
BackgroundIncomplete cytokinesis/binucleation in mammals
Fortier, M., Celton‐Morizur, S., & Desdouets, C. (2016) · Methods in cell biology · doi:10.1016/bs.mcb.2016.04.006 · Cited by 25
Self-citationTaniguchi, K., Kokuryo, A., Imano, T., Nakagoshi, H., & Adachi-Yamada, T. (2018) · Zoological Science · doi:10.2108/zs170188 · Cited by 16
p38α regulates actin cytoskeleton and cytokinesis in hepatocytes during development and aging
Tormos, A. M., Rius‐Pérez, S., Jorques, M., Rada, P., Ramirez, L., Valverde, Á. M., Nebreda, Á. R., Sastre, J., & Taléns‐Visconti, R. (2017) · PLoS ONE · doi:10.1371/journal.pone.0171738 · Cited by 18
Cellular polyploidy in organ homeostasis and regeneration
Fang, J., de Bruin, A., Villunger, A., Schiffelers, R. M., Lei, Z., & Sluijter, J. P. G. (2022) · Protein & Cell · doi:10.1093/procel/pwac064 · Cited by 19
“…robust proliferative ability before weaning and this capacity gradually goes down with time; by coincidence, polyploid hepatocytes occur at weaning in rodents and increase in parallel with age (Kudryavtsev et al., 1993; Margall-Ducos et al., 2007; Celton-Morizur et al., 2009; Duncan et al., 2010).”
Influential[Cross-talk between insulin signaling and cell proliferation pathways].
Burnol, A.-F., Morzyglod, L., & Popineau, L. (2013) · Annales d'Endocrinologie · doi:10.1016/j.ando.2013.02.003 · Cited by 13
Binucleated human hepatocytes arise through late cytokinetic regression during endomitosis M phase
Darmasaputra, G., Geerlings, C. C., Lopes, S. M. C. D. S., Clevers, H. C., & Galli, M. (2024) · The Journal of Cell Biology · doi:10.1083/jcb.202403020 · Cited by 16
“To determine if WNT-mediated repression of binucleation in Hep-Orgs is dependent on E2F7 and E2F8, as has been reported in mouse hepatocytes (Celton-Morizur et al., 2009; Margall-Ducos et al., 2007; Pandit et al., 2012), we used the CRISPR-based cytosine base editor system (Komor et al., 2016;…”
BackgroundMethodInfluentialSsu72 Dual-Specific Protein Phosphatase: From Gene to Diseases
Hwang, S., Kim, M., & Lee, C. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22073791 · Cited by 11
“Indeed, a recent study supports the above notion that there is a direct association between abnormal hepatic polyploidy and the development of NAFLD [97].”
BackgroundInfluentialVanhaesebroeck, B., Bilanges, B., Madsen, R. R., Dale, K. L., Lau, E., & Vladimirou, E. (2019) · Biomolecules · doi:10.3390/biom9080331 · Cited by 11
“program, leading to the generation of binucleated tetraploid cells [80].”
The Ploidy State as a Determinant of Hepatocyte Proliferation
Wilson, S. R., & Duncan, A. W. (2023) · Seminars in Liver Disease · doi:10.1055/a-2211-2144 · Cited by 16
“22,23 Thecellular effects of insulin are mediated by the PI3K/AKT pathway, which antagonize RHOA and negatively regulate actin cytoskeleton polarization ( ► Fig.”
BackgroundThe Controversial Role of Polyploidy in Hepatocellular Carcinoma
Wang, N., Hao, F., Shi, Y., & Wang, J. (2021) · OncoTargets and Therapy · doi:10.2147/ott.s340435 · Cited by 13
Hepatic regenerative medicine: exploiting the liver's will to live.
Monga, S. (2014) · American Journal of Pathology · doi:10.1016/j.ajpath.2013.11.004 · Cited by 11
“Intriguingly, a major pathway implicated in this process is insulin-Akt signaling.(13) Although liver is normally composed of polyploid hepatocytes, specific situations can lead to additional changes in ploidy, including iron overload, altered redox state of a cell, and partial hepatectomy.”
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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