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 ORCID:

Qi-Hua HUA

https://orcid.org/0009-0007-8599-5834

Zan HUANG

https://orcid.org/0000-0001-5623-6950

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Journal of Zhejiang University SCIENCE B 2025 Vol.26 No.9 P.843-862

http://doi.org/10.1631/jzus.B2400127


Endomitosis: a new cell fate in the cell cycle leading to polyploidy in megakaryocytes and hepatocytes


Author(s):  Qi-Hua HUA, Xuechun ZHANG, Ruifeng TIAN, Zhigang SHE, Zan HUANG

Affiliation(s):  College of Life Sciences, Key Laboratory of Cell Homeostasis of Hubei Province, Wuhan University, Wuhan 430060, China; more

Corresponding email(s):   z-huang@whu.edu.cn

Key Words:  Polyploidy, Endomitosis, Megakaryocyte, Hepatocyte, Cell cycle, Tetraploidy checkpoint, Whole-genome doubling


Qi-Hua HUA, Xuechun ZHANG, Ruifeng TIAN, Zhigang SHE, Zan HUANG. Endomitosis: a new cell fate in the cell cycle leading to polyploidy in megakaryocytes and hepatocytes[J]. Journal of Zhejiang University Science B, 2025, 26(9): 843-862.

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A1 - Zan HUANG
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DOI - 10.1631/jzus.B2400127


Abstract: 
megakaryocytes and hepatocytes are unique cells in mammals that undergo polyploidization through endomitosis in terminal differentiation. Many polyploidization regulators and underlying mechanisms have been reported, most of which are tightly coupled with development, organogenesis, and cell differentiation. However, the nature of endomitosis, which involves successful entry into and exit from mitosis without complete cytokinesis, has not yet been fully elucidated. We highlight that endomitosis is a new cell fate in the cell cycle, and tetraploidy is a critical stage at the bifurcation of cell fate decision. This review summarizes the recent research progress in this area and provides novel insights into how cells manipulate mitosis toward endomitosis. Endomitotic cells can evade the tetraploidy restrictions and proceed to multiple rounds of the cell cycle. This knowledge not only deepens our understanding of endomitosis as a fundamental biological process but also offers new perspectives on the physiological and pathophysiological implications of polyploidization.

核内有丝分裂:细胞周期中的新细胞命运-以巨核细胞和肝细胞的多倍体化为例

花启华1,张雪纯1,田瑞锋2,折志刚2,3,黄赞1
1武汉大学生命科学学院,湖北省细胞稳态重点实验室,中国武汉市,430060
2武汉大学人民医院心内科,中国武汉市,430060
3赣南医学院心脑血管疾病预防与治疗教育部重点实验室,赣南创新与转化医学研究所,中国赣州市,341000
摘要:巨核细胞和肝细胞在哺乳动物中具有独特性,它们在终末分化过程中通过核内有丝分裂实现多倍体化。许多多倍体化的调控因子和潜在机制已被报道,其中大多数与发育、器官发生和细胞分化紧密相关。然而,核内有丝分裂的本质尚未完全阐明,该过程包括成功进入和退出有丝分裂而不发生完全的胞质分裂。本文强调,核内有丝分裂是细胞周期中一种新的细胞命运,而四倍体阶段则是细胞命运决定的关键时期。本文综述了该领域的最新研究进展,并为细胞如何操控有丝分裂以实现核内有丝分裂提供了新见解,即核内有丝分裂细胞能够规避四倍体检查点的限制,继续进行多次全基因组加倍。这些发现不仅加深了我们对核内有丝分裂作为一种基本生物学过程的理解,还为多倍体化的生理和病理学意义提供了新的视角。

关键词:多倍体;核内有丝分裂;巨核细胞;肝细胞;细胞周期;四倍体检查点;全基因组加倍

Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article

Reference

[1]AbmayrSM, PavlathGK, 2012. Myoblast fusion: lessons from flies and mice. Development, 139(4):641-656.

[2]AlbertinW, MarulloP, 2012. Polyploidy in fungi: evolution after whole-genome duplication. Proc Biol Sci, 279(1738):2497-2509.

[3]Alfonso-PérezT, HaywardD, HolderJ, et al., 2019. MAD1-dependent recruitment of CDK1-CCNB1 to kinetochores promotes spindle checkpoint signaling. J Cell Biol, 218(4):1108-1117.

[4]AndreassenPR, LohezOD, LacroixFB, et al., 2001. Tetraploid state induces p53-dependent arrest of nontransformed mammalian cells in G1. Mol Biol Cell, 12(5):1315-1328.

[5]Antony-DebréI, BluteauD, ItzyksonR, et al., 2012. MYH10 protein expression in platelets as a biomarker of RUNX1 and FLI1 alterations. Blood, 120(13):2719-2722.

[6]ApostolidisPA, WoulfeDS, ChavezM, et al., 2012. Role of tumor suppressor p53 in megakaryopoiesis and platelet function. Exp Hematol, 40(2):131-142.e4.

[7]AvanziMP, GoldbergF, DavilaJ, et al., 2014. Rho kinase inhibition drives megakaryocyte polyploidization and proplatelet formation through MYC and NFE2 downregulation. Br J Haematol, 164(6):867-876.

[8]AylonY, OrenM, 2011. p53: guardian of ploidy. Mol Oncol, 5(4):315-323.

[9]AylonY, MichaelD, ShmueliA, et al., 2006. A positive feedback loop between the P53 and Lats2 tumor suppressors prevents tetraploidization. Genes Dev, 20(19):2687-2700.

[10]BacciniV, RoyL, VitratN, et al., 2001. Role of p21Cip1/Waf1 in cell-cycle exit of endomitotic megakaryocytes. Blood, 98(12):3274-3282.

[11]BadirouI, PanJJ, LegrandC, et al., 2014. Carboxyl-terminal-dependent recruitment of nonmuscle myosin II to megakaryocyte contractile ring during polyploidization. Blood, 124(16):2564-2568.

[12]BaenaE, GandarillasA, VallespinósM, et al., 2005. c-Myc regulates cell size and ploidy but is not essential for postnatal proliferation in liver. Proc Natl Acad Sci USA, 102(20):7286-7291.

[13]BentleyAM, NormandG, HoytJ, et al., 2007. Distinct sequence elements of cyclin B1 promote localization to chromatin, centrosomes, and kinetochores during mitosis. Mol Biol Cell, 18(12):4847-4858.

[14]BermejoR, VilaboaN, CalésC, 2002. Regulation of CDC6, geminin, and CDT1 in human cells that undergo polyploidization. Mol Biol Cell, 13(11):3989-4000.

[15]BerthebaudM, RiviereC, JarrierP, et al., 2005. RGS16 is a negative regulator of SDF-1-CXCR4 signaling in megakaryocytes. Blood, 106(9):2962-2968.

[16]BertoliC, SkotheimJM, de BruinRAM, 2013. Control of cell cycle transcription during G1 and S phases. Nat Rev Mol Cell Biol, 14(8):518-528.

[17]BesancenotR, ChalignéR, TonettiC, et al., 2010. A senescence-like cell-cycle arrest occurs during megakaryocytic maturation: implications for physiological and pathological megakaryocytic proliferation. PLoS Biol, 8(9):e1000476.

[18]BielskiCM, ZehirA, PensonAV, et al., 2018. Genome doubling shapes the evolution and prognosis of advanced cancers. Nat Genet, 50(8):1189-1195.

[19]BluteauD, LordierL, di StefanoA, et al., 2009. Regulation of megakaryocyte maturation and platelet formation. J Thromb Haemost, 7(Suppl 1):227-234.

[20]BluteauD, GlembotskyAC, RaimbaultA, et al., 2012. Dysmegakaryopoiesis of FPD/AML pedigrees with constitutional RUNX1 mutations is linked to myosin II deregulated expression. Blood, 120(13):2708-2718.

[21]BluteauD, BalduiniA, BalaynN, et al., 2014. Thrombocytopenia-associated mutations in the ANKRD26 regulatory region induce MAPK hyperactivation. J Clin Invest, 124(2):580-591.

[22]Bou-NaderM, CarusoS, DonneR, et al., 2020. Polyploidy spectrum: a new marker in HCC classification. Gut, 69(2):355-364.

[23]BritoDA, RiederCL, 2006. Mitotic checkpoint slippage in humans occurs via cyclin B destruction in the presence of an active checkpoint. Curr Biol, 16(12):1194-1200.

[24]BurigottoM, MattiviA, MiglioratiD, et al., 2021. Centriolar distal appendages activate the centrosome-PIDDosome-p53 signalling axis via ANKRD26. EMBO J, 40(4):e104844.

[25]BursteinSA, MeiRL, HenthornJ, et al., 1992. Leukemia inhibitory factor and interleukin-11 promote maturation of murine and human megakaryocytes in vitro. J Cell Physiol, 153(2):305-312.

[26]CarriereR, 1967. Polyploid cell reproduction in normal adult rat liver. Exp Cell Res, 46(3):533-540.

[27]Celton-MorizurS, DesdouetsC, 2010. Polyploidization of liver cells. In: Poon RYC (Ed.), Polyploidization and Cancer. Springer, New York, p.123-135.

[28]Celton-MorizurS, MerlenG, CoutonD, et al., 2009. The insulin/Akt pathway controls a specific cell division program that leads to generation of binucleated tetraploid liver cells in rodents. J Clin Invest, 119(7):1880-1887.

[29]Celton-MorizurS, MerlenG, CoutonD, et al., 2010. Polyploidy and liver proliferation: central role of insulin signaling. Cell Cycle, 9(3):460-466.

[30]ChagraouiH, KassoufM, BanerjeeS, et al., 2011. SCL-mediated regulation of the cell-cycle regulator p21 is critical for murine megakaryopoiesis. Blood, 118(3):723-735.

[31]ChanprasertS, GeddisAE, BarrogaC, et al., 2006. Thrombopoietin (TPO) induces c-myc expression through a PI3K- and MAPK-dependent pathway that is not mediated by Akt, PKCζ or mTOR in TPO-dependent cell lines and primary megakaryocytes. Cell Signal, 18(8):1212-1218.

[32]ChenHZ, OusephMM, LiJ, et al., 2012. Canonical and atypical E2Fs regulate the mammalian endocycle. Nat Cell Biol, 14(11):1192-1202.

[33]ChenQ, ZhangXY, JiangQ, et al., 2008. Cyclin B1 is localized to unattached kinetochores and contributes to efficient microtubule attachment and proper chromosome alignment during mitosis. Cell Res, 18(2):268-280.

[34]ChengEC, LuoQ, BrusciaEM, et al., 2009. Role for MKL1 in megakaryocytic maturation. Blood, 113(12):2826-2834.

[35]ConnerEA, LemmerER, SánchezA, et al., 2003. E2F1 blocks and c-Myc accelerates hepatic ploidy in transgenic mouse models. Biochem Biophys Res Commun, 302(1):114-120.

[36]CrispinoJD, WeissMJ, 2014. Erythro-megakaryocytic transcription factors associated with hereditary anemia. Blood, 123(20):3080-3088.

[37]CrossSM, SanchezCA, MorganCA, et al., 1995. A p53-dependent mouse spindle checkpoint. Science, 267(5202):1353-1356.

[38]DarmasaputraGS, GeerlingsCC, Chuva de Sousa LopesSM, et al., 2024. Binucleated human hepatocytes arise through late cytokinetic regression during endomitosis M phase. J Cell Biol, 223(8):e202403020.

[39]DehnAS, LosickVP, 2022. Binucleation ramps up gene expression meeting the physiological demands of an organism. PLoS Biol, 20(5):e3001639.

[40]de Santis PuzzoniaM, CozzolinoAM, GrassiG, et al., 2016. TGFbeta induces binucleation/polyploidization in hepatocytes through a Src-dependent cytokinesis failure. PLoS ONE, 11(11):e0167158.

[41]DirilMK, RatnacaramCK, PadmakumarVC, et al., 2012. Cyclin-dependent kinase 1 (Cdk1) is essential for cell division and suppression of DNA re-replication but not for liver regeneration. Proc Natl Acad Sci USA, 109(10):3826-3831.

[42]DonneR, Saroul-AïnamaM, CordierP, et al., 2020. Polyploidy in liver development, homeostasis and disease. Nat Rev Gastroenterol Hepatol, 17(7):391-405.

[43]DrayerAL, OlthofSGM, VellengaE, 2006. Mammalian target of rapamycin is required for thrombopoietin-induced proliferation of megakaryocyte progenitors. Stem Cells, 24(1):105-114.

[44]DuncanAW, TaylorMH, HickeyRD, et al., 2010. The ploidy conveyor of mature hepatocytes as a source of genetic variation. Nature, 467(7316):707-710.

[45]EbaughFGJr, BirdRM, 1951. The normal megakaryocyte concentration in aspirated human bone marrow. Blood, 6(1):75-80.

[46]ElagibKE, BrockA, ClementelliCM, et al., 2022. Relieving DYRK1A repression of MKL1 confers an adult-like phenotype to human infantile megakaryocytes. J Clin Invest, 132(19):e154839.

[47]EliadesA, PapadantonakisN, RavidK, 2010. New roles for cyclin E in megakaryocytic polyploidization. J Biol Chem, 285(24):18909-18917.

[48]EliadesA, PapadantonakisN, MatsuuraS, et al., 2013. Megakaryocyte polyploidy is inhibited by lysyl oxidase propeptide. Cell Cycle, 12(8):1242-1250.

[49]EngelFB, SchebestaM, KeatingMT, 2006. Anillin localization defect in cardiomyocyte binucleation. J Mol Cell Cardiol, 41(4):601-612.

[50]EvansLT, AnglenT, ScottP, et al., 2021. ANKRD26 recruits PIDD1 to centriolar distal appendages to activate the PIDDosome following centrosome amplification. EMBO J, 40(4):e105106.

[51]FavaLL, SchulerF, SladkyV, et al., 2017. The PIDDosome activates p53 in response to supernumerary centrosomes. Genes Dev, 31(1):34-45.

[52]FededaJP, GerlichDW, 2012. Molecular control of animal cell cytokinesis. Nat Cell Biol, 14(5):440-447.

[53]FortierM, Celton-MorizurS, DesdouetsC, 2017. Incomplete cytokinesis/binucleation in mammals: the powerful system of hepatocytes. Methods Cell Biol, 137:119-142.

[54]FoxDT, DuronioRJ, 2013. Endoreplication and polyploidy: insights into development and disease. Development, 140(1):3-12.

[55]FuhrkenPG, ApostolidisPA, LindseyS, et al., 2008. Tumor suppressor protein p53 regulates megakaryocytic polyploidization and apoptosis. J Biol Chem, 283(23):15589-15600.

[56]FurukawaY, KikuchiJ, NakamuraM, et al., 2000. Lineage-specific regulation of cell cycle control gene expression during haematopoietic cell differentiation. Br J Haematol, 110(3):663-673.

[57]GanPH, PattersonM, SucovHM, 2020. Cardiomyocyte polyploidy and implications for heart regeneration. Annu Rev Physiol, 82:45-61.

[58]GanemNJ, StorchovaZ, PellmanD, 2007. Tetraploidy, aneuploidy and cancer. Curr Opin Genet Dev, 17(2):157-162.

[59]GanemNJ, CornilsH, ChiuSY, et al., 2014. Cytokinesis failure triggers Hippo tumor suppressor pathway activation. Cell, 158(4):833-848.

[60]GaoY, SmithE, KerE, et al., 2012. Role of RhoA-specific guanine exchange factors in regulation of endomitosis in megakaryocytes. Dev Cell, 22(3):573-584.

[61]GeddisAE, KaushanskyK, 2006. Endomitotic megakaryocytes form a midzone in anaphase but have a deficiency in cleavage furrow formation. Cell Cycle, 5(5):538-545.

[62]GeddisAE, FoxNE, TkachenkoE, et al., 2007. Endomitotic megakaryocytes that form a bipolar spindle exhibit cleavage furrow ingression followed by furrow regression. Cell Cycle, 6(4):455-460.

[63]GembleS, WardenaarR, KeuperK, et al., 2022. Genetic instability from a single S phase after whole-genome duplication. Nature, 604(7904):146-151.

[64]GengY, YuQY, SicinskaE, et al., 2003. Cyclin E ablation in the mouse. Cell, 114(4):431-443.

[65]GentricG, DesdouetsC, 2014. Polyploidization in liver tissue. Am J Pathol, 184(2):322-331.

[66]GentricG, MailletV, ParadisV, et al., 2015. Oxidative stress promotes pathologic polyploidization in nonalcoholic fatty liver disease. J Clin Invest, 125(3):981-992.

[67]GiammonaLM, PanugantiS, KemperJM, et al., 2009. Mechanistic studies on the effects of nicotinamide on megakaryocytic polyploidization and the roles of NAD+ levels and SIRT inhibition. Exp Hematol, 37(11):1340-1352.e3.

[68]GillesL, GuièzeR, BluteauD, et al., 2008. P19INK4D links endomitotic arrest and megakaryocyte maturation and is regulated by AML-1. Blood, 111(8):4081-4091.

[69]GillesL, BluteauD, BoukourS, et al., 2009. MAL/SRF complex is involved in platelet formation and megakaryocyte migration by regulating MYL9 (MLC2) and MMP9. Blood, 114(19):4221-4232.

[70]GoldensonB, KirsammerG, StankiewiczMJ, et al., 2015. Aurora kinase A is required for hematopoiesis but is dispensable for murine megakaryocyte endomitosis and differentiation. Blood, 125(13):2141-2150.

[71]GuerrieroR, MattiaG, TestaU, et al., 2001. Stromal cell-derived factor 1α increases polyploidization of megakaryocytes generated by human hematopoietic progenitor cells. Blood, 97(9):2587-2595.

[72]GuerrieroR, ParoliniI, TestaU, et al., 2006. Inhibition of TPO-induced MEK or mTOR activity induces opposite effects on the ploidy of human differentiating megakaryocytes. J Cell Sci, 119(4):744-752.

[73]GuidottiJE, BrégerieO, RobertA, et al., 2003. Liver cell polyploidization: a pivotal role for binuclear hepatocytes. J Biol Chem, 278(21):19095-19101.

[74]HamadaT, MöhleR, HesselgesserJ, et al., 1998. Transendothelial migration of megakaryocytes in response to stromal cell-derived factor 1 (SDF-1) enhances platelet formation. J Exp Med, 188(3):539-548.

[75]HeibT, HermannsHM, ManukjanG, et al., 2021. RhoA/Cdc42 signaling drives cytoplasmic maturation but not endomitosis in megakaryocytes. Cell Rep, 35(6):109102.

[76]HerriageHC, HuangYT, CalviBR, 2024. The antagonistic relationship between apoptosis and polyploidy in development and cancer. Semin Cell Dev Biol, 156:35-43.

[77]HsuSH, DelgadoER, OteroPA, et al., 2016. MicroRNA-122 regulates polyploidization in the murine liver. Hepatology, 64(2):599-615.

[78]HuangH, YuM, AkieTE, et al., 2009. Differentiation-dependent interactions between RUNX-1 and FLI-1 during megakaryocyte development. Mol Cell Biol, 29(15):4103-4115.

[79]HuangZ, RichmondTD, MunteanAG, et al., 2007. STAT1 promotes megakaryopoiesis downstream of GATA-1 in mice. J Clin Invest, 117(12):3890-3899.

[80]HuangZ, DoreLC, LiZ, et al., 2009. GATA-2 reinforces megakaryocyte development in the absence of GATA-1. Mol Cell Biol, 29(18):5168-5180.

[81]Iancu-RubinC, NasrallahCA, AtwehGF, 2005. Stathmin prevents the transition from a normal to an endomitotic cell cycle during megakaryocytic differentiation. Cell Cycle, 4(12):1774-1782.

[82]Iancu-RubinC, GajzerD, TripodiJ, et al., 2011. Down-regulation of stathmin expression is required for megakaryocyte maturation and platelet production. Blood, 117(17):4580-4589.

[83]JinYH, AnbarchianT, WuP, et al., 2022. Wnt signaling regulates hepatocyte cell division by a transcriptional repressor cascade. Proc Natl Acad Sci USA, 119(30):e2203849119.

[84]KatsudaT, HosakaK, MatsuzakiJ, et al., 2020. Transcriptomic dissection of hepatocyte heterogeneity: linking ploidy, zonation, and stem/progenitor cell characteristics. Cell Mol Gastroenterol Hepatol, 9(1):161-183.

[85]KaushanskyK, 2016. Thrombopoietin and its receptor in normal and neoplastic hematopoiesis. Thromb J, 14(Suppl 1):40.

[86]KikuchiJ, FurukawaY, IwaseS, et al., 1997. Polyploidization and functional maturation are two distinct processes during megakaryocytic differentiation: involvement of cyclin-dependent kinase inhibitor p21 in polyploidization. Blood, 89(11):3980-3990.

[87]KimSH, JeonY, KimHS, et al., 2016. Hepatocyte homeostasis for chromosome ploidization and liver function is regulated by Ssu72 protein phosphatase. Hepatology, 63(1):247-259.

[88]KobayashiS, TeramuraM, ItoK, et al., 1998. Transcription factor NF-E2 is essential for the polyploidization of a human megakaryoblastic cell line, Meg-J. Biochem Biophys Res Commun, 247(1):65-69.

[89]KosoffRE, AslanJE, KostyakJC, et al., 2015. Pak2 restrains endomitosis during megakaryopoiesis and alters cytoskeleton organization. Blood, 125(19):2995-3005.

[90]KrauseDS, CrispinoJD, 2013. Molecular pathways: induction of polyploidy as a novel differentiation therapy for leukemia. Clin Cancer Res, 19(22):6084-6088.

[91]KudryavtsevBN, KudryavtsevaMV, SakutaGA, et al., 1993. Human hepatocyte polyploidization kinetics in the course of life cycle. Virchows Arch B Cell Pathol Incl Mol Pathol, 64(6):387-393.

[92]KurinnaS, StrattonSA, CobanZ, et al., 2013. p53 regulates a mitotic transcription program and determines ploidy in normal mouse liver. Hepatology, 57(5):2004-2013.

[93]KuterDJ, GminskiDM, RosenbergRD, 1992. Transforming growth factor beta inhibits megakaryocyte growth and endomitosis. Blood, 79(3):619-626.

[94]LacroixB, MaddoxAS, 2012. Cytokinesis, ploidy and aneuploidy. J Pathol, 226(2):338-351.

[95]LambutaRA, NanniL, LiuYL, et al., 2023. Whole-genome doubling drives oncogenic loss of chromatin segregation. Nature, 615(7954):925-933.

[96]LeeBC, ZhouYF, BrescianiE, et al., 2023. A RUNX1-FPDMM rhesus macaque model reproduces the human phenotype and predicts challenges to curative gene therapies. Blood, 141(3):231-237.

[97]LeeDH, ParkJO, KimTS, et al., 2016. LATS-YAP/TAZ controls lineage specification by regulating TGFβ signaling and Hnf4α expression during liver development. Nat Commun, 7:11961.

[98]LeeK, AhnHS, EstevezB, et al., 2023. RUNX1-deficient human megakaryocytes demonstrate thrombopoietic and platelet half-life and functional defects. Blood, 141(3):260-270.

[99]LefrançaisE, Ortiz-MuñozG, CaudrillierA, et al., 2017. The lung is a site of platelet biogenesis and a reservoir for haematopoietic progenitors. Nature, 544(7648):105-109.

[100]LeoneM, MusaG, EngelFB, 2018. Cardiomyocyte binucleation is associated with aberrant mitotic microtubule distribution, mislocalization of RhoA and IQGAP3, as well as defective actomyosin ring anchorage and cleavage furrow ingression. Cardiovasc Res, 114(8):1115-1131.

[101]Leysi-DerilouY, RobertA, DuchesneC, et al., 2010. Polyploid megakaryocytes can complete cytokinesis. Cell Cycle, 9(13):2589-2599.

[102]LiD, CenJ, ChenXT, et al., 2013. Hepatic loss of survivin impairs postnatal liver development and promotes expansion of hepatic progenitor cells in mice. Hepatology, 58(6):2109-2121.

[103]LiangCQ, ZhouDC, PengWT, et al., 2022. FoxO3 restricts liver regeneration by suppressing the proliferation of hepatocytes. NPJ Regen Med, 7:33.

[104]LinH, HuangYS, FustinJM, et al., 2021. Hyperpolyploidization of hepatocyte initiates preneoplastic lesion formation in the liver. Nat Commun, 12:645.

[105]LinYH, ZhangSY, ZhuM, et al., 2020. Mice with increased numbers of polyploid hepatocytes maintain regenerative capacity but develop fewer hepatocellular carcinomas following chronic liver injury. Gastroenterology, 158(6):1698-1712.e14.

[106]LindseyS, PapoutsakisET, 2011. The aryl hydrocarbon receptor (AHR) transcription factor regulates megakaryocytic polyploidization. Br J Haematol, 152(4):469-484.

[107]LiuL, WenQ, GongR, et al., 2014. PSTPIP2 dysregulation contributes to aberrant terminal differentiation in GATA-1-deficient megakaryocytes by activating LYN. Cell Death Dis, 5(1):e988.

[108]LordierL, JalilA, AuradeF, et al., 2008. Megakaryocyte endomitosis is a failure of late cytokinesis related to defects in the contractile ring and Rho/Rock signaling. Blood, 112(8):3164-3174.

[109]LordierL, ChangYH, JalilA, et al., 2010. Aurora B is dispensable for megakaryocyte polyploidization, but contributes to the endomitotic process. Blood, 116(13):2345-2355.

[110]LordierL, BluteauD, JalilA, et al., 2012. RUNX1-induced silencing of non-muscle myosin heavy chain IIB contributes to megakaryocyte polyploidization. Nat Commun, 3:717.

[111]LoutitJF, NisbetNW, 1982. The origin of osteoclasts. Immunobiology, 161(3-4):193-203.

[112]MailletV, BoussettaN, LeclercJ, et al., 2018. LKB1 as a gatekeeper of hepatocyte proliferation and genomic integrity during liver regeneration. Cell Rep, 22(8):1994-2005.

[113]ManchadoE, GuillamotM, de CárcerG, et al., 2010. Targeting mitotic exit leads to tumor regression in vivo: modulation by Cdk1, Mastl, and the PP2A/B55α,δ phosphatase. Cancer Cell, 18(6):641-654.

[114]ManicG, CorradiF, SistiguA, et al., 2017. Molecular regulation of the spindle assembly checkpoint by kinases and phosphatases. In: Galluzzi L (Ed.), International Review of Cell and Molecular Biology. Academic Press, Cambridge, p.105-161.

[115]ManneBK, CampbellRA, BhatlekarS, et al., 2022. MAPK-interacting kinase 1 regulates platelet production, activation, and thrombosis. Blood, 140(23):2477-2489.

[116]Margall-DucosG, Celton-MorizurS, CoutonD, et al., 2007. Liver tetraploidization is controlled by a new process of incomplete cytokinesis. J Cell Sci, 120(20):3633-3639.

[117]MargolisRL, LohezOD, AndreassenPR, 2003. G1 tetraploidy checkpoint and the suppression of tumorigenesis. J Cell Biochem, 88(4):673-683.

[118]MayhewCN, BoscoEE, FoxSR, et al., 2005. Liver-specific pRB loss results in ectopic cell cycle entry and aberrant ploidy. Cancer Res, 65(11):4568-4577.

[119]MazharianA, WatsonSP, SéverinS, 2009. Critical role for ERK1/2 in bone marrow and fetal liver-derived primary megakaryocyte differentiation, motility, and proplatelet formation. Exp Hematol, 37(10):1238-1249.e5.

[120]MazziS, LordierL, DebiliN, et al., 2018. Megakaryocyte and polyploidization. Exp Hematol, 57:1-13.

[121]MazziS, DessenP, VieiraM, et al., 2021. Dual role of EZH2 in megakaryocyte differentiation. Blood, 138(17):1603-1614.

[122]McCrannDJ, EliadesA, MakitaloM, et al., 2009. Differential expression of NADPH oxidases in megakaryocytes and their role in polyploidy. Blood, 114(6):1243-1249.

[123]McKenneyC, LendnerY, ZunigaAG, et al., 2024. CDK4/6 activity is required during G2 arrest to prevent stress-induced endoreplication. Science, 384(6695):eadi2421.

[124]MercherT, CornejoMG, SearsC, et al., 2008. Notch signaling specifies megakaryocyte development from hematopoietic stem cells. Cell Stem Cell, 3(3):314-326.

[125]MinamishimaYA, NakayamaK, NakayamaKI, 2002. Recovery of liver mass without proliferation of hepatocytes after partial hepatectomy in Skp2-deficient mice. Cancer Res, 62(4):995-999.

[126]MorenoE, MatondoAB, BongiovanniL, et al., 2022. Inhibition of polyploidization in Pten-deficient livers reduces steatosis. Liver Int, 42(11):2442-2452.

[127]MunteanAG, PangLY, PonczM, et al., 2007. Cyclin D-Cdk4 is regulated by GATA-1 and required for megakaryocyte growth and polyploidization. Blood, 109(12):5199-5207.

[128]MusacchioA, SalmonED, 2007. The spindle-assembly checkpoint in space and time. Nat Rev Mol Cell Biol, 8(5):379-393.

[129]NagataY, MuroY, TodokoroK, 1997. Thrombopoietin-induced polyploidization of bone marrow megakaryocytes is due to a unique regulatory mechanism in late mitosis. J Cell Biol, 139(2):449-457.

[130]NakaoT, GeddisAE, FoxNE, et al., 2008. PI3K/Akt/FOXO3a pathway contributes to thrombopoietin-induced proliferation of primary megakaryocytes in vitro and in vivo via modulation of p27Kip1. Cell Cycle, 7(2):257-266.

[131]NevzorovaYA, TschaharganehD, GasslerN, et al., 2009. Aberrant cell cycle progression and endoreplication in regenerating livers of mice that lack a single E-type cyclin. Gastroenterology, 137(2):691-703.e6.

[132]NottermanD, YoungS, WaingerB, et al., 1998. Prevention of mammalian DNA reduplication, following the release from the mitotic spindle checkpoint, requires p53 protein, but not p53-mediated transcriptional activity. Oncogene, 17(21):2743-2751.

[133]OnoY, WangYH, SuzukiH, et al., 2012. Induction of functional platelets from mouse and human fibroblasts by p45NF-E2/Maf. Blood, 120(18):3812-3821.

[134]ØvrebøJI, EdgarBA, 2018. Polyploidy in tissue homeostasis and regeneration. Development, 145(14):dev156034.

[135]PanditSK, WestendorpB, NantasantiS, et al., 2012. E2F8 is essential for polyploidization in mammalian cells. Nat Cell Biol, 14(11):1181-1191.

[136]PanditSK, WestendorpB, de BruinA, 2013. Physiological significance of polyploidization in mammalian cells. Trends Cell Biol, 23(11):556-566.

[137]PapadantonakisN, MakitaloM, McCrannD, et al., 2008. Direct visualization of the endomitotic cell cycle in living megakaryocytes: differential patterns in low and high ploidy cells. Cell Cycle, 7(15):2352-2356.

[138]PetersJM, 2006. The anaphase promoting complex/cyclosome: a machine designed to destroy. Nat Rev Mol Cell Biol, 7(9):644-656.

[139]QuintonRJ, DidomizioA, VittoriaMA, et al., 2021. Whole-genome doubling confers unique genetic vulnerabilities on tumour cells. Nature, 590(7846):492-497.

[140]RaguC, BoukourS, ElainG, et al., 2010. The serum response factor (SRF)/megakaryocytic acute leukemia (MAL) network participates in megakaryocyte development. Leukemia, 24(6):1227-1230.

[141]RaslovaH, BacciniV, LoussaiefL, et al., 2006. Mammalian target of rapamycin (mTOR) regulates both proliferation of megakaryocyte progenitors and late stages of megakaryocyte differentiation. Blood, 107(6):2303-2310.

[142]RaslovaH, KauffmannA, SekkaiD, et al., 2007. Interrelation between polyploidization and megakaryocyte differentiation: a gene profiling approach. Blood, 109(8):3225-3234.

[143]RavidK, LuJ, ZimmetJM, et al., 2002. Roads to polyploidy: the megakaryocyte example. J Cell Physiol, 190(1):7-20.

[144]ReedFE, EskowNM, MinE, et al., 2022. Structure-function analysis of the role of megakaryoblastic leukemia 1 in megakaryocyte polyploidization. Haematologica, 107(12):2972-2976.

[145]RichterML, DeligiannisIK, YinK, et al., 2021. Single-nucleus RNA-seq2 reveals functional crosstalk between liver zonation and ploidy. Nat Commun, 12:4264.

[146]RiosAC, FuNY, JamiesonPR, et al., 2016. Essential role for a novel population of binucleated mammary epithelial cells in lactation. Nat Commun, 7:11400.

[147]RouyezMC, BoucheronC, GisselbrechtS, et al., 1997. Control of thrombopoietin-induced megakaryocytic differentiation by the mitogen-activated protein kinase pathway. Mol Cell Biol, 17(9):4991-5000.

[148]RoyA, LordierL, MazziS, et al., 2016a. Activity of nonmuscle myosin II isoforms determines localization at the cleavage furrow of megakaryocytes. Blood, 128(26):3137-3145.

[149]RoyA, LordierL, Pioche-DurieuC, et al., 2016b. Uncoupling of the Hippo and Rho pathways allows megakaryocytes to escape the tetraploid checkpoint. Haematologica, 101(12):1469-1478.

[150]RoyL, CoullinP, VitratN, et al., 2001. Asymmetrical segregation of chromosomes with a normal metaphase/anaphase checkpoint in polyploid megakaryocytes. Blood, 97(8):2238-2247.

[151]Sakaue-SawanoA, KurokawaH, MorimuraT, et al., 2008. Visualizing spatiotemporal dynamics of multicellular cell-cycle progression. Cell, 132(3):487-498.

[152]Sakaue-SawanoA, HoshidaT, YoM, et al., 2013. Visualizing developmentally programmed endoreplication in mammals using ubiquitin oscillators. Development, 140(22):4624-4632.

[153]SantamaríaD, BarrièreC, CerqueiraA, et al., 2007. Cdk1 is sufficient to drive the mammalian cell cycle. Nature, 448(7155):811-815.

[154]Sanz-GómezN, González-ÁlvarezM, de Las RivasJ, et al., 2023. Whole-genome doubling as a source of cancer: how, when, where, and why? Front Cell Dev Biol, 11:1209136.

[155]ScheininTM, KoivuniemiAP, 1963. Megakaryocytes in the pulmonary circulation. Blood, 22(1):82-87.

[156]SheahanS, BellamyCO, TreanorL, et al., 2004. Additive effect of p53, p21 and Rb deletion in triple knockout primary hepatocytes. Oncogene, 23(8):1489-1497.

[157]ShivdasaniRA, RosenblattMF, Zucker-FranklinD, et al., 1995. Transcription factor NF-E2 is required for platelet formation independent of the actions of thrombopoeitin/MGDF in megakaryocyte development. Cell, 81(5):695-704.

[158]SinhaD, DuijfPHG, KhannaKK, 2019. Mitotic slippage: an old tale with a new twist. Cell Cycle, 18(1):7-15.

[159]SladkyVC, KnappK, SoratroiC, et al., 2020a. E2F-family members engage the PIDDosome to limit hepatocyte ploidy in liver development and regeneration. Dev Cell, 52(3):335-349.e7.

[160]SladkyVC, KnappK, SzaboTG, et al., 2020b. PIDDosome-induced p53-dependent ploidy restriction facilitates hepatocarcinogenesis. EMBO Rep, 21(12):e50893.

[161]SladkyVC, EichinF, ReibergerT, et al., 2021. Polyploidy control in hepatic health and disease. J Hepatol, 75(5):1177-1191.

[162]SladkyVC, AkbariH, Tapias-GomezD, et al., 2022. Centriole signaling restricts hepatocyte ploidy to maintain liver integrity. Genes Dev, 36(13-14):843-856.

[163]SmithEC, TeixeiraAM, ChenRC, et al., 2013. Induction of megakaryocyte differentiation drives nuclear accumulation and transcriptional function of MKL1 via actin polymerization and RhoA activation. Blood, 121(7):1094-1101.

[164]StegnerD, VaneeuwijkJMM, AngayO, et al., 2017. Thrombopoiesis is spatially regulated by the bone marrow vasculature. Nat Commun, 8:127.

[165]SunL, TanP, YapC, et al., 2004. In vitro biological characteristics of human cord blood-derived megakaryocytes. Ann Acad Med Singap, 33(5):570-575.

[166]SunS, ZimmetJM, ToselliP, et al., 2001. Overexpression of cyclin D1 moderately increases ploidy in megakaryocytes. Haematologica, 86(1):17-23.

[167]SunXQ, LuB, HanCJ, et al., 2017. ANP32A dysregulation contributes to abnormal megakaryopoiesis in acute megakaryoblastic leukemia. Blood Cancer J, 7(12):661.

[168]SuraneniPK, CrispinoJD, 2016. The Hippo-p53 pathway in megakaryopoiesis. Haematologica, 101(12):1446-1448.

[169]SvartmanM, StoneG, StanyonR, 2005. Molecular cytogenetics discards polyploidy in mammals. Genomics, 85(4):425-430.

[170]TaniguchiT, EndoH, ChikatsuN, et al., 1999. Expression of p21Cip1/Waf1/Sdi1 and p27Kip1 cyclin-dependent kinase inhibitors during human hematopoiesis. Blood, 93(12):4167-4178.

[171]TeofiliL, MartiniM, di MarioA, et al., 2001. Expression of p15ink4b gene during megakaryocytic differentiation of normal and myelodysplastic hematopoietic progenitors. Blood, 98(2):495-497.

[172]TijssenMR, GhevaertC, 2013. Transcription factors in late megakaryopoiesis and related platelet disorders. J Thromb Haemost, 11(4):593-604.

[173]TijssenMR, CvejicA, JoshiA, et al., 2011. Genome-wide analysis of simultaneous GATA1/2, RUNX1, FLI1, and SCL binding in megakaryocytes identifies hematopoietic regulators. Dev Cell, 20(5):597-609.

[174]TongW, LodishHF, 2004. Lnk inhibits Tpo-mpl signaling and Tpo-mediated megakaryocytopoiesis. J Exp Med, 200(5):569-580.

[175]TrakalaM, PartidaD, Salazar-RoaM, et al., 2015a. Activation of the endomitotic spindle assembly checkpoint and thrombocytopenia in Plk1-deficient mice. Blood, 126(14):1707-1714.

[176]TrakalaM, Rodríguez-AcebesS, MarotoM, et al., 2015b. Functional reprogramming of polyploidization in megakaryocytes. Dev Cell, 32(2):155-167.

[177]UetakeY, SluderG, 2004. Cell cycle progression after cleavage failure: mammalian somatic cells do not possess a “tetraploidy checkpoint”. J Cell Biol, 165(5):609-615.

[178]VainchenkerW, RaslovaH, 2020. Megakaryocyte polyploidization: role in platelet production. Platelets, 31(6):707-716.

[179]VainchenkerW, ArkounB, Basso-ValentinaF, et al., 2021. Role of Rho-GTPases in megakaryopoiesis. Small GTPases, 12(5-6):399-415.

[180]van de PeerY, MizrachiE, MarchalK, 2017. The evolutionary significance of polyploidy. Nat Rev Genet, 18(7):411-424.

[181]van RijnberkLM, Barrull-MascaróR, van der PalenRL, et al., 2022. Endomitosis controls tissue-specific gene expression during development. PLoS Biol, 20(5):e3001597.

[182]VilaboaN, BermejoR, MartinezP, et al., 2004. A novel E2 box-GATA element modulates Cdc6 transcription during human cells polyploidization. Nucleic Acids Res, 32(21):6454-6467.

[183]VitaleI, GalluzziL, CastedoM, et al., 2011. Mitotic catastrophe: a mechanism for avoiding genomic instability. Nat Rev Mol Cell Biol, 12(6):385-392.

[184]VitratN, Cohen-SolalK, PiqueC, et al., 1998. Endomitosis of human megakaryocytes are due to abortive mitosis. Blood, 91(10):3711-3723.

[185]WangMJ, ChenF, LauJTY, et al., 2017. Hepatocyte polyploidization and its association with pathophysiological processes. Cell Death Dis, 8(5):e2805.

[186]WangQ, LiuTY, FangYQ, et al., 2004. BUBR1 deficiency results in abnormal megakaryopoiesis. Blood, 103(4):1278-1285.

[187]WangZ, ZhangY, KamenD, et al., 1995. Cyclin D3 is essential for megakaryocytopoiesis. Blood, 86(10):3783-3788.

[188]Weiss-GayetM, StarckJ, ChaabouniA, et al., 2016. Notch stimulates both self-renewal and lineage plasticity in a subset of murine CD9High committed megakaryocytic progenitors. PLoS ONE, 11(4):e0153860.

[189]WenQ, LeungC, HuangZ, et al., 2009. Survivin is not required for the endomitotic cell cycle of megakaryocytes. Blood, 114(1):153-156.

[190]WenQ, GoldensonB, SilverSJ, et al., 2012. Identification of regulators of polyploidization presents therapeutic targets for treatment of AMKL. Cell, 150(3):575-589.

[191]WenQJ, YangQ, GoldensonB, et al., 2015. Targeting megakaryocytic-induced fibrosis in myeloproliferative neoplasms by AURKA inhibition. Nat Med, 21(12):1473-1480.

[192]WilkinsonPD, DelgadoER, AlencastroF, et al., 2019. The polyploid state restricts hepatocyte proliferation and liver regeneration in mice. Hepatology, 69(3):1242-1258.

[193]WongC, StearnsT, 2005. Mammalian cells lack checkpoints for tetraploidy, aberrant centrosome number, and cytokinesis failure. BMC Cell Biol, 6:6.

[194]WuH, WadeM, KrallL, et al., 1996. Targeted in vivo expression of the cyclin-dependent kinase inhibitor p21 halts hepatocyte cell-cycle progression, postnatal liver development and regeneration. Genes Dev, 10(3):245-260.

[195]WurzenbergerC, GerlichDW, 2011. Phosphatases: providing safe passage through mitotic exit. Nat Rev Mol Cell Biol, 12(8):469-482.

[196]YuCJ, YangQ, ChenYH, et al., 2016. Tyrosine 625 plays a key role and cooperates with tyrosine 630 in MPL W515L-induced signaling and myeloproliferative neoplasms. Cell Biosci, 6:34.

[197]YuFX, ZhaoB, PanupinthuN, et al., 2012. Regulation of the Hippo-YAP pathway by G-protein-coupled receptor signaling. Cell, 150(4):780-791.

[198]ZackTI, SchumacherSE, CarterSL, et al., 2013. Pan-cancer patterns of somatic copy number alteration. Nat Genet, 45(10):1134-1140.

[199]ZangCZ, LuytenA, ChenJ, et al., 2016. NF-E2, FLI1 and RUNX1 collaborate at areas of dynamic chromatin to activate transcription in mature mouse megakaryocytes. Sci Rep, 6:30255.

[200]ZengJK, HillsSA, OzonoE, et al., 2023. Cyclin E-induced replicative stress drives p53-dependent whole-genome duplication. Cell, 186(3):528-542.e14.

[201]ZhangSH, ChenQH, LiuQX, et al., 2017. Hippo signaling suppresses cell ploidy and tumorigenesis through Skp2. Cancer Cell, 31(5):669-684.e7.

[202]ZhangSY, NguyenLH, ZhouKJ, et al., 2018a. Knockdown of Anillin actin binding protein blocks cytokinesis in hepatocytes and reduces liver tumor development in mice without affecting regeneration. Gastroenterology, 154(5):1421-1434.

[203]ZhangSY, ZhouKJ, LuoX, et al., 2018b. The polyploid state plays a tumor-suppressive role in the liver. Dev Cell, 44(4):447-459.e5.

[204]ZhangSY, LinYH, TarlowB, et al., 2019. The origins and functions of hepatic polyploidy. Cell Cycle, 18(12):1302-1315.

[205]ZhangY, WangZY, RavidK, 1996. The cell cycle in polyploid megakaryocytes is associated with reduced activity of cyclin B1-dependent Cdc2 kinase. J Biol Chem, 271(8):4266-4272.

[206]ZhangY, SunS, WangZY, et al., 2002. Signaling by the Mpl receptor involves IKK and NF-κB. J Cell Biochem, 85(3):523-535.

[207]ZielkeN, EdgarBA, DePamphilisML, 2013. Endoreplication. Cold Spring Harb Perspect Biol, 5(1):a012948.

[208]ZimmetJ, RavidK, 2000. Polyploidy: occurrence in nature, mechanisms, and significance for the megakaryocyte-platelet system. Exp Hematol, 28(1):3-16.

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