Cellular polyploidy in organ homeostasis and regeneration

Abstract

Polyploid cells, which contain more than one set of chromosome pairs, are very common in nature. Polyploidy can provide cells with several potential benefits over their diploid counterparts, including an increase in cell size, contributing to organ growth and tissue homeostasis, and improving cellular robustness via increased tolerance to genomic stress and apoptotic signals. Here, we focus on why polyploidy in the cell occurs and which stress responses and molecular signals trigger cells to become polyploid. Moreover, we discuss its crucial roles in cell growth and tissue regeneration in the heart, liver, and other tissues.

Keywords

cellular polyploidy / tissue regeneration / cardiac regeneration / liver regeneration

References

[1] Adler CP, Friedburg H. Myocardial DNA content, ploidy level and cell number in geriatric hearts: post-mortem examinations of human myocardium in old age. J Mol Cell Cardiol 1986;18:39–53.

[2] Adler CP, Friedburg H, Herget GW et al. Variability of cardiomyocyte DNA content, ploidy level and nuclear number in mammalian hearts. Virchows Arch 1996;429:159–164.

[3] Ahuja P, Perriard E, Trimble W et al. Probing the role of septins in cardiomyocytes. Exp Cell Res 2006;312:1598–1609.

[4] Aix E, Gutierrez-Gutierrez O, Sanchez-Ferrer C et al. Postnatal telomere dysfunction induces cardiomyocyte cell-cycle arrest through p21 activation. J Cell Biol 2016;213:571–583.

[5] Al-Hussaini H, Kam JH, Vugler A et al. Mature retinal pigment epithelium cells are retained in the cell cycle and proliferate in vivo. Mol Vis 2008;14:1784–1791.

[6] Ali SR, Hippenmeyer S, Saadat LV et al. Existing cardiomyocytes generate cardiomyocytes at a low rate after birth in mice. Proc Natl Acad Sci U S A 2014;111:8850–8855.

[7] Anatskaya OV, Vinogradov AE. Paradoxical relationship between protein content and nucleolar activity in mammalian cardiomyocytes. Genome 2004;47:565–578.

[8] Anatskaya OV, Vinogradov AE. Genome multiplication as adaptation to tissue survival: evidence from gene expression in mammalian heart and liver. Genomics 2007;89:70–80.

[9] Anatskaya OV, Vinogradov AE, Kudryavtsev BN. Hepatocyte polyploidy and metabolism/life-history traits: hypotheses testing. J Theor Biol 1994;168:191–199.

[10] Anatskaya OV, Vinogradov AE, Kudryavtsev BN. Cardiomyocyte ploidy levels in birds with different growth rates. J Exp Zool 2001;289:48–58.

[11] Anti M, Marra G, Rapaccini GL et al. DNA ploidy pattern in human chronic liver diseases and hepatic nodular lesions. Flow cytometric analysis on echo-guided needle liver biopsy. Cancer 1994;73:281–288.

[12] Banerjee MR, Wagner JE. Gene amplification in mammary gland at differentiation. Biochem Biophys Res Commun 1972;49:480–487.

[13] Banerjee MR, Wagner JE, Kinder DL. DNA synthesis in the absence of cell reproduction during functional differentiation of mouse mammary gland. Life Sci II 1971;10:867–877.

[14] Barbera A, Giraud GD, Reller MD et al. Right ventricular systolic pressure load alters myocyte maturation in fetal sheep. Am J Physiol Regul Integr Comp Physiol 2000;279:R1157–R1164.

[15] Barnard DR, Lange B, Alonzo TA et al. Acute myeloid leukemia and myelodysplastic syndrome in children treated for cancer: comparison with primary presentation. Blood 2002;100:427–434.

[16] Bartelds B, Knoester H, Smid GB et al. Perinatal changes in myocardial metabolism in lambs. Circulation 2000;102:926–931.

[17] Beltrami AP, Urbanek K, Kajstura J et al. Evidence that human cardiac myocytes divide after myocardial infarction. N Engl J Med 2001;344:1750–1757.

[18] Bensley JG, De Matteo R, Harding R et al. Three-dimensional direct measurement of cardiomyocyte volume, nuclearity, and ploidy in thick histological sections. Sci Rep 2016;6:23756.

[19] Bergmann O, Bhardwaj RD, Bernard S et al. Evidence for cardiomyocyte renewal in humans. Science 2009;324:98–102.

[20] Bergmann O, Zdunek S, Felker A et al. Dynamics of Cell Generation and Turnover in the Human Heart. Cell 2015;161:1566–1575.

[21] Bersell K, Arab S, Haring B et al. Neuregulin1/ErbB4 signaling induces cardiomyocyte proliferation and repair of heart injury. Cell 2009;138:257–270.

[22] Bettencourt-Dias M, Mittnacht S, Brockes JP. Heterogeneous proliferative potential in regenerative adult newt cardiomyocytes. J Cell Sci 2003;116:4001–4009.

[23] Bicknell KA, Coxon CH, Brooks G. Forced expression of the cyclin B1-CDC2 complex induces proliferation in adult rat cardiomyocytes. Biochem J 2004;382:411–416.

[24] Bogart JP. Evolutionary implications of polyploidy in amphibians and reptiles. Basic Life Sci 1979;13:341–378.

[25] Brito DA, Rieder CL. Mitotic checkpoint slippage in humans occurs via cyclin B destruction in the presence of an active checkpoint. Curr Biol 2006;16:1194–1200.

[26] Brodsky V, Sarkisov DS, Arefyeva AM et al. Polyploidy in cardiac myocytes of normal and hypertrophic human hearts; range of values. Virchows Arch 1994;424:429–435.

[27] Burigotto M, Mattivi A, Migliorati D et al. Centriolar distal appendages activate the centrosome-PIDDosome-p53 signalling axis via ANKRD26. EMBO J 2021;40:e104844.

[28] Cao J, Wang J, Jackman CP et al. Tension creates an endoreplication wavefront that leads regeneration of epicardial tissue. Dev Cell 2017;42:600–615

[29] Carlton JG, Caballe A, Agromayor M et al. ESCRT-III governs the Aurora B-mediated abscission checkpoint through CHMP4C. Science 2012;336:220–225.

[30] Celton-Morizur S, Merlen G, Couton D et al. The insulin/Akt pathway controls a specific cell division program that leads to generation of binucleated tetraploid liver cells in rodents. J Clin Invest 2009;119:1880–1887.

[31] Celton-Morizur S, Merlen G, Couton D et al. Polyploidy and liver proliferation: central role of insulin signaling. Cell Cycle 2010;9:460–466.

[32] Chandra M, Frith CH. Spontaneous neoplasms in aged CD-1 mice. Toxicol Lett 1992;61:67–74.

[33] Chattergoon NN, Giraud GD, Louey S et al. Thyroid hormone drives fetal cardiomyocyte maturation. FASEB J 2012a;26:397–408.

[34] Chattergoon NN, Louey S, Stork P et al. Mid-gestation ovine cardiomyocytes are vulnerable to mitotic suppression by thyroid hormone. Reprod Sci 2012b;19:642–649.

[35] Chen HZ, Ouseph MM, Li J et al. Canonical and atypical E2Fs regulate the mammalian endocycle. Nat Cell Biol 2012;14:1192–1202.

[36] Chen M, Rajapakse D, Fraczek M et al. Retinal pigment epithelial cell multinucleation in the aging eye - a mechanism to repair damage and maintain homoeostasis. Aging Cell 2016;15:436–445.

[37] Chen Y, Hata T, Rehman F et al. Visualization of Hepatocellular Regeneration in Mice After Partial Hepatectomy. J Surg Res 2019;235:494–500.

[38] Chipchase MD, O’Neill M, Melton DW. Characterization of premature liver polyploidy in DNA repair (Ercc1)-deficient mice. Hepatology 2003;38:958–966.

[39] Clubb FJ Jr., Bishop SP. Formation of binucleated myocardial cells in the neonatal rat. An index for growth hypertrophy. Lab Invest 1984;50:571–577.

[40] Conner EA, Lemmer ER, Sanchez A et al. E2F1 blocks and c-Myc accelerates hepatic ploidy in transgenic mouse models. Biochem Biophys Res Commun 2003;302:114–120.

[41] Cookson SJ, Radziejwoski A, Granier C. Cell and leaf size plasticity in Arabidopsis: what is the role of endoreduplication? Plant Cell Environ 2006;29:1273–1283.

[42] Crosio C, Fimia GM, Loury R et al. Mitotic phosphorylation of histone H3: spatio-temporal regulation by mammalian Aurora kinases. Mol Cell Biol 2002;22:874–885.

[43] D’Uva G, Aharonov A, Lauriola M et al. ERBB2 triggers mammalian heart regeneration by promoting cardiomyocyte dedifferentiation and proliferation. Nat Cell Biol 2015;17:627–638.

[44] Davoli T, Denchi EL, de Lange T. Persistent telomere damage induces bypass of mitosis and tetraploidy. Cell 2010;141:81–93.

[45] De Santis Puzzonia M, Cozzolino AM, Grassi G et al. TGFbeta Induces Binucleation/Polyploidization in Hepatocytes through a Src-Dependent Cytokinesis Failure. PLoS One 2016;11:e0167158.

[46] Dikovskaya D, Schiffmann D, Newton IP et al. Loss of APC induces polyploidy as a result of a combination of defects in mitosis and apoptosis. J Cell Biol 2007;176:183–195.

[47] Di Micco R, Fumagalli M, Cicalese A et al. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature 2006;444:638–642.

[48] Diril MK, Ratnacaram CK, Padmakumar VC et al. 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 U S A 2012;109:3826–3831.

[49] Di Stefano V, Giacca M, Capogrossi MC et al. Knockdown of cyclin-dependent kinase inhibitors induces cardiomyocyte re-entry in the cell cycle. J Biol Chem 2011;286:8644–8654.

[50] Drenckhahn JD, Strasen J, Heinecke K et al. Impaired myocardial development resulting in neonatal cardiac hypoplasia alters postnatal growth and stress response in the heart. Cardiovasc Res 2015;106:43–54.

[51] Duchrow M, Schluter C, Wohlenberg C et al. Molecular characterization of the gene locus of the human cell proliferation-associated nuclear protein defined by monoclonal antibody Ki-67. Cell Prolif 1996;29:1–12.

[52] Duncan AW, Hickey RD, Paulk NK et al. Ploidy reductions in murine fusion-derived hepatocytes. PLoS Genet 2009;5:e1000385.

[53] Duncan AW, Taylor MH, Hickey RD et al. The ploidy conveyor of mature hepatocytes as a source of genetic variation. Nature 2010;467:707–710.

[54] Duncan AW, Hanlon Newell AE, Bi W et al. Aneuploidy as a mechanism for stress-induced liver adaptation. J Clin Invest 2012a;122:3307–3315.

[55] Duncan AW, Hanlon Newell AE, Smith L et al. Frequent aneuploidy among normal human hepatocytes. Gastroenterology 2012b;142:25–28.

[56] Engel FB, Schebesta M, Duong MT et al. p38 MAP kinase inhibition enables proliferation of adult mammalian cardiomyocytes. Genes Dev 2005;19:1175–1187.

[57] Engel FB, Schebesta M, Keating MT. Anillin localization defect in cardiomyocyte binucleation. J Mol Cell Cardiol 2006;41:601–612.

[58] Epstein CJ. Cell size, nuclear content, and the development of polyploidy in the Mammalian liver. Proc Natl Acad Sci U S A 1967;57:327–334.

[59] Erokhina IL, Selivanova GV, Vlasova TD et al. Ultrastructure and biosynthetic activity of polyploid atrial myocytes in patients with mitral valve disease. Acta Histochem Suppl 1992;42:293–299.

[60] Faggioli F, Sacco MG, Susani L et al. Cell fusion is a physiological process in mouse liver. Hepatology 2008;48:1655–1664.

[61] Faggioli F, Vezzoni P, Montagna C. Single-cell analysis of ploidy and centrosomes underscores the peculiarity of normal hepatocytes. PLoS One 2011;6:e26080.

[62] Fan C, Chen H, Liu K et al. Fibrinogen-like protein 2 contributes to normal murine cardiomyocyte maturation and heart development. Exp Physiol 2021;106:1559–1571.

[63] Fava LL, Schuler F, Sladky V et al. The PIDDosome activates p53 in response to supernumerary centrosomes. Genes Dev 2017;31:34–45.

[64] Finegood DT, Scaglia L, Bonner-Weir S. Dynamics of beta-cell mass in the growing rat pancreas. Estimation with a simple mathematical model. Diabetes 1995;44:249–256.

[65] Font-Burgada J, Shalapour S, Ramaswamy S et al. Hybrid periportal hepatocytes regenerate the injured liver without giving rise to cancer. Cell 2015;162:766–779.

[66] Freije A, Ceballos L, Coisy M et al. Cyclin E drives human keratinocyte growth into differentiation. Oncogene 2012;31:5180–5192.

[67] Freije A, Molinuevo R, Ceballos L et al. Inactivation of p53 in human keratinocytes leads to squamous differentiation and shedding via replication stress and mitotic slippage. Cell Rep 2014;9:1349–1360.

[68] Fujiwara T, Bandi M, Nitta M et al. Cytokinesis failure generating tetraploids promotes tumorigenesis in p53-null cells. Nature 2005;437:1043–1047.

[69] Gabisonia K, Prosdocimo G, Aquaro GD et al. MicroRNA therapy stimulates uncontrolled cardiac repair after myocardial infarction in pigs. Nature 2019;569:418–422.

[70] Gandarillas A, Davies D, Blanchard JM. Normal and c-Myc-promoted human keratinocyte differentiation both occur via a novel cell cycle involving cellular growth and endoreplication. Oncogene 2000;19:3278–3289.

[71] Gandillet A, Alexandre E, Royer C et al. Hepatocyte ploidy in regenerating livers after partial hepatectomy, drug-induced necrosis, and cirrhosis. Eur Surg Res 2003;35:148–160.

[72] Ganem NJ, Storchova Z, Pellman D. Tetraploidy, aneuploidy and cancer. Curr Opin Genet Dev 2007;17:157–162.

[73] Ganem NJ, Godinho SA, Pellman D. A mechanism linking extra centrosomes to chromosomal instability. Nature 2009;460:278–282.

[74] Gentric G, Maillet V, Paradis V et al. Oxidative stress promotes pathologic polyploidization in nonalcoholic fatty liver disease. J Clin Invest 2015;125:981–992.

[75] Gerdes J, Schwab U, Lemke H et al. Production of a mouse monoclonal antibody reactive with a human nuclear antigen associated with cell proliferation. Int J Cancer 1983;31:13–20.

[76] Gerlyng P, Grotmol T, Erikstein B et al. Reduced proliferative activity of polyploid cells in primary hepatocellular carcinoma. Carcinogenesis 1992;13:1795–1801.

[77] Gerlyng P, Abyholm A, Grotmol T et al. Binucleation and polyploidization patterns in developmental and regenerative rat liver growth. Cell Prolif 1993;26:557–565.

[78] Gilsbach R, Schwaderer M, Preissl S et al. Distinct epigenetic programs regulate cardiac myocyte development and disease in the human heart in vivo. Nat Commun 2018;9:391.

[79] Gimelbrant A, Hutchinson JN, Thompson BR et al. Widespread monoallelic expression on human autosomes. Science 2007;318:1136–1140.

[80] Gonzalez-Rosa JM, Sharpe M, Field D et al. Myocardial polyploidization creates a barrier to heart regeneration in zebrafish. Dev Cell 2018;44:433–446

[81] Gorla GR, Malhi H, Gupta S. Polyploidy associated with oxidative injury attenuates proliferative potential of cells. J Cell Sci 2001;114:2943–2951.

[82] Grendler J, Lowgren S, Mills M et al. Wound-induced polyploidization is driven by Myc and supports tissue repair in the presence of DNA damage. Development 2019;146.

[83] Guc-Scekic M, Milasin J, Stevanovic M et al. Tetraploidy in a 26-month-old girl (cytogenetic and molecular studies). Clin Genet 2002;61:62–65.

[84] Guidotti JE, Bregerie O, Robert A et al. Liver cell polyploidization: a pivotal role for binuclear hepatocytes. J Biol Chem 1909278:5–19101.

[85] Gujabidze N, Rukhadze R. Influence of experimental hyperthyreosis on hepatocytes’ cell cycle in white mice. Georgian Med News 2006;131:112–115.

[86] Hagemann S, Wohlschlaeger J, Bertram S et al. Loss of Survivin influences liver regeneration and is associated with impaired Aurora B function. Cell Death Differ 2013;20:834–844.

[87] Han L, Choudhury S, Mich-Basso JD et al. Lamin B2 levels regulate polyploidization of cardiomyocyte nuclei and myocardial regeneration. Dev Cell 2020;53:42–59

[88] Hanovice NJ, Leach LL, Slater K et al. Regeneration of the zebrafish retinal pigment epithelium after widespread genetic ablation. PLoS Genet 2019;15:e1007939.

[89] Hart M, Adams SD, Draviam VM. Multinucleation associated DNA damage blocks proliferation in p53-compromised cells. Commun Biol 2021;4:451.

[90] Heinke P, Rost F, Rode J et al. Diploid hepatocytes drive physiological liver renewal in adult humans. Cell Syst 2022;13:499–507

[91] Herget GW, Neuburger M, Plagwitz R et al. DNA content, ploidy level and number of nuclei in the human heart after myocardial infarction. Cardiovasc Res 1997;36:45–51.

[92] Hesse M, Raulf A, Pilz GA et al. Direct visualization of cell division using high-resolution imaging of M-phase of the cell cycle. Nat Commun 2012;3:1076.

[93] Hightower E, Cabanillas ME, Fuller GN et al. Phospho-histone H3 (pHH3) immuno-reactivity as a prognostic marker in non-functioning pituitary adenomas. Pituitary 2012;15:556–561.

[94] Hirose K, Payumo AY, Cutie S et al. Evidence for hormonal control of heart regenerative capacity during endothermy acquisition. Science 2019;364:184–188.

[95] Hixon ML, Muro-Cacho C, Wagner MW et al. Akt1/PKB upregulation leads to vascular smooth muscle cell hypertrophy and polyploidization. J Clin Invest 2000;106:1011–1020.

[96] Hsu SH, Delgado ER, Otero PA et al. MicroRNA-122 regulates polyploidization in the murine liver. Hepatology 2016;64:599–615.

[97] Huppertz B, Frank HG, Kingdom JC et al. Villous cytotrophoblast regulation of the syncytial apoptotic cascade in the human placenta. Histochem Cell Biol 1998;110:495–508.

[98] Iglesias-Ara A, Zenarruzabeitia O, Buelta L et al. E2F1 and E2F2 prevent replicative stress and subsequent p53-dependent organ involution. Cell Death Differ 2015;22:1577–1589.

[99] Jacobs PA, Szulman AE, Funkhouser J et al. Human triploidy: relationship between parental origin of the additional haploid complement and development of partial hydatidiform mole. Ann Hum Genet 1982;46:223–231.

[100] Jiang YH, Zhu Y, Chen S et al. Re-enforcing hypoxia-induced polyploid cardiomyocytes enter cytokinesis through activation of beta-catenin. Sci Rep 2019;9:17865.

[101] Jiang YH, Wang HL, Peng J et al. Multinucleated polyploid cardiomyocytes undergo an enhanced adaptability to hypoxia via mitophagy. J Mol Cell Cardiol 2020;138:115–135.

[102] Jonker SS, Zhang L, Louey S et al. Myocyte enlargement, differentiation, and proliferation kinetics in the fetal sheep heart. J Appl Physiol (1985) 2007a;102:1130–1142.

[103] Jonker SS, Faber JJ, Anderson DF et al. Sequential growth of fetal sheep cardiac myocytes in response to simultaneous arterial and venous hypertension. Am J Physiol Regul Integr Comp Physiol 2007b;292:R913–R919.

[104] Jonker SS, Giraud MK, Giraud GD et al. Cardiomyocyte enlargement, proliferation and maturation during chronic fetal anaemia in sheep. Exp Physiol 2010;95:131–139.

[105] Jonsdottir AB, Stefansson OA, Bjornsson J et al. Tetraploidy in BRCA2 breast tumours. Eur J Cancer 2012;48:305–310.

[106] Kang MJ, Kim JS, Chae SW et al. Cyclins and cyclin dependent kinases during cardiac development. Mol Cells 1997;7:360–366.

[107] Kang J, Hwang I, Yoo C et al. Nab-paclitaxel plus gemcitabine versus FOLFIRINOX as the first-line chemotherapy for patients with metastatic pancreatic cancer: retrospective analysis. Invest New Drugs 2018;36:732–741.

[108] Ke Q, Gong L, Zhu X et al. Multinucleated Retinal Pigment Epithelial Cells Adapt to Vision and Exhibit Increased DNA Damage Response. Cells 2022;11.

[109] Kemp K, Gordon D, Wraith DC et al. Fusion between human mesenchymal stem cells and rodent cerebellar Purkinje cells. Neuropathol Appl Neurobiol 2011;37:166–178.

[110] Kemp K, Gray E, Wilkins A et al. Purkinje cell fusion and binucleate heterokaryon formation in multiple sclerosis cerebellum. Brain 2012;135:2962–2972.

[111] Kent LN, Rakijas JB, Pandit SK et al. E2f8 mediates tumor suppression in postnatal liver development. J Clin Invest 2016;126:2955–2969.

[112] Kern L, Spreckels J, Nist A et al. Altered glycogen metabolism causes hepatomegaly following an Atg7 deletion. Cell Tissue Res 2016;366:651–665.

[113] Kim SH, Jeon Y, Kim HS et al. Hepatocyte homeostasis for chromosome ploidization and liver function is regulated by Ssu72 protein phosphatase. Hepatology 2016;63:247–259.

[114] Klapholz B, Dietrich BH, Schaffner C et al. CAF-1 is required for efficient replication of euchromatic DNA in Drosophila larval endocycling cells. Chromosoma 2009;118:235–248.

[115] Knouse KA, Wu J, Whittaker CA et al. Single cell sequencing reveals low levels of aneuploidy across mammalian tissues. Proc Natl Acad Sci U S A 2014 111:13409–13414.

[116] Knouse KA, Lopez KE, Bachofner M et al. Chromosome Segregation Fidelity in Epithelia Requires Tissue Architecture. Cell 2018;175:200–211

[117] Kops GJ, Foltz DR, Cleveland DW. Lethality to human cancer cells through massive chromosome loss by inhibition of the mitotic checkpoint. Proc Natl Acad Sci U S A 2004;101:8699–8704.

[118] Kreutz C, MacNelly S, Follo M et al. Hepatocyte ploidy is a diversity factor for liver homeostasis. Front Physiol 2017;8:862.

[119] Kriesten K. [Relative incidence of mitosis and binucleated cells, nuclear volume and nucleolar rate per nucleus in the mammary gland eipithelium of the mouse during differentiation in the gestational and lactation phase]. Gegenbaurs Morphol Jahrb 1984;130:307–314.

[120] Kudryavtsev BN, Kudryavtseva MV, Sakuta GA et al. Human hepatocyte polyploidization kinetics in the course of life cycle. Virchows Arch B Cell Pathol Incl Mol Pathol 1993;64:387–393.

[121] Kurinna S, Stratton SA, Coban Z et al. p53 regulates a mitotic transcription program and determines ploidy in normal mouse liver. Hepatology 2013;57:2004–2013.

[122] Lai SL, Marin-Juez R, Moura PL et al. Reciprocal analyses in zebrafish and medaka reveal that harnessing the immune response promotes cardiac regeneration. Elife 2017;6:1–20.

[123] Lamar ZS, Fino N, Palmer J et al. Dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (EPOCH) with or without rituximab as first-line therapy for aggressive non-Hodgkin lymphoma. Clin Lymphoma Myeloma Leuk 2016;16:76–81.

[124] Lazzerini Denchi E, Celli G, de Lange T. Hepatocytes with extensive telomere deprotection and fusion remain viable and regenerate liver mass through endoreduplication. Genes Dev 2006;20:2648–2653.

[125] Leitch AR, Leitch IJ. Genomic plasticity and the diversity of polyploid plants. Science 2008;320:481–483.

[126] Leone M, Engel FB. Pseudo-bipolar spindle formation and cell division in postnatal binucleated cardiomyocytes. J Mol Cell Cardiol 2019;134:69–73.

[127] Levkau B, Schafers M, Wohlschlaeger J et al. Survivin determines cardiac function by controlling total cardiomyocyte number. Circulation 2008;117:1583–1593.

[128] Li F, Wang X, Capasso JM et al. Rapid transition of cardiac myocytes from hyperplasia to hypertrophy during postnatal development. J Mol Cell Cardiol 1996;28:1737–1746.

[129] Li D, Cen J, Chen X et al. Hepatic loss of survivin impairs postnatal liver development and promotes expansion of hepatic progenitor cells in mice. Hepatology 2013;58:2109–2121.

[130] Li D, Liu Y, Pei C et al. miR-285-Yki/Mask double-negative feedback loop mediates blood-brain barrier integrity in Drosophila. Proc Natl Acad Sci U S A 2017;114:E2365–E2374.

[131] Li W, Dai Y, Shi B et al. LRPPRC sustains Yap-P27-mediated cell ploidy and P62-HDAC6-mediated autophagy maturation and suppresses genome instability and hepatocellular carcinomas. Oncogene 2020;39:3879–3892.

[132] Lilly MA, Spradling AC. The Drosophila endocycle is controlled by Cyclin E and lacks a checkpoint ensuring S-phase completion. Genes Dev 1996;10:2514–2526.

[133] Lin YH, Zhang S, Zhu M et al. Mice with increased numbers of polyploid hepatocytes maintain regenerative capacity but develop fewer hepatocellular carcinomas following chronic liver injury. Gastroenterology 2020;158:1698–1712

[134] Liu Z, Yue S, Chen X et al. Regulation of cardiomyocyte polyploidy and multinucleation by CyclinG1. Circ Res 2010;106:1498–1506.

[135] Losick VP, Fox DT, Spradling AC. Polyploidization and cell fusion contribute to wound healing in the adult Drosophila epithelium. Curr Biol 2013;23:2224–2232.

[136] Losick VP, Jun AS, Spradling AC. Wound-induced polyploidization: regulation by hippo and JNK signaling and conservation in mammals. PLoS One 2016;11:e0151251.

[137] Lu P, Prost S, Caldwell sH et al. Microarray analysis of gene expression of mouse hepatocytes of different ploidy. Mamm Genome 2007;18:617–626.

[138] Mable BK, Otto SP. Masking and purging mutations following EMS treatment in haploid, diploid and tetraploid yeast (Saccharomyces cerevisiae). Genet Res 2001;77:9–26.

[139] Madra S, Styles J, Smith AG. Perturbation of hepatocyte nuclear populations induced by iron and polychlorinated biphenyls in C57BL/10ScSn mice during carcinogenesis. Carcinogenesis 1995;16:719–727.

[140] Mahmoud AI, Kocabas F, Muralidhar SA et al. Meis1 regulates postnatal cardiomyocyte cell cycle arrest. Nature 2013;497:249–253.

[141] Maines JZ, Stevens LM, Tong X et al. Drosophila dMyc is required for ovary cell growth and endoreplication. Development 2004;131:775–786.

[142] Malhi H, Gorla GR, Irani AN et al. Cell transplantation after oxidative hepatic preconditioning with radiation and ischemia-reperfusion leads to extensive liver repopulation. Proc Natl Acad Sci U S A 2002;99:13114–13119.

[143] Mansilla S, Priebe W, Portugal J. Mitotic catastrophe results in cell death by caspase-dependent and caspase-independent mechanisms. Cell Cycle 2006;5:53–60.

[144] Margall-Ducos G, Celton-Morizur S, Couton D et al. Liver tetraploidization is controlled by a new process of incomplete cytokinesis. J Cell Sci 2007;120:3633–3639.

[145] Martin NC, McCullough CT, Bush PG et al. Functional analysis of mouse hepatocytes differing in DNA content: volume, receptor expression, and effect of IFNgamma. J Cell Physiol 2002;191:138–144.

[146] Martynova MG, Selivanova GV, Vlasova TD. Ploidy levels and the number of nuclei in cardiomyocytes of the lamprey and fish. Tsitologiia 2002;44:387–391.

[147] Matondo RB, Moreno E, Toussaint MJM et al. Atypical E2f functions are critical for pancreas polyploidization. PLoS One 2018;13:e0190899.

[148] Matsumoto T, Wakefield L, Tarlow BD et al. In vivo lineage tracing of polyploid hepatocytes reveals extensive proliferation during liver regeneration. Cell Stem Cell 2020;26:34–47

[149] Maurici D, Perez-Atayde A, Grier HE et al. Frequency and implications of chromosome 8 and 12 gains in Ewing sarcoma. Cancer Genet Cytogenet 1998;100:106–110.

[150] Mayhew CN, Bosco EE, Fox SR et al. Liver-specific pRB loss results in ectopic cell cycle entry and aberrant ploidy. Cancer Res 2005;65:4568–4577.

[151] McConnell MJ, Lindberg MR, Brennand KJ et al. Mosaic copy number variation in human neurons. Science 2013;342:632–637.

[152] Meckert PC, Rivello HG, Vigliano C et al. Endomitosis and polyploidization of myocardial cells in the periphery of human acute myocardial infarction. Cardiovasc Res 2005;67:116–123.

[153] Mehrotra S, Maqbool SB, Kolpakas A et al. Endocycling cells do not apoptose in response to DNA rereplication genotoxic stress. Genes Dev 2008;22:3158–3171.

[154] Meissner HP. Electrophysiological evidence for coupling between beta cells of pancreatic islets. Nature 1976;262:502–504.

[155] Michel L, Diaz-Rodriguez E, Narayan G et al. Complete loss of the tumor suppressor MAD2 causes premature cyclin B degradation and mitotic failure in human somatic cells. Proc Natl Acad Sci U S A 2004;101:4459–4464.

[156] Minamishima YA, Nakayama K, Nakayama K. Recovery of liver mass without proliferation of hepatocytes after partial hepatectomy in Skp2-deficient mice. Cancer Res 2002;62:995–999.

[157] Miyaoka Y, Ebato K, Kato H et al. Hypertrophy and unconventional cell division of hepatocytes underlie liver regeneration. Curr Biol 2012;22:1166–1175.

[158] Mollova M, Bersell K, Walsh S et al. Cardiomyocyte proliferation contributes to heart growth in young humans. Proc Natl Acad Sci U S A 2013;110:1446–1451.

[159] Muramatsu Y, Yamada T, Moralejo DH et al. Increased polyploid incidence is associated with abnormal copper accumulation in the liver of LEC mutant rat. Res Commun Mol Pathol Pharmacol 2000;107:129–136.

[160] Nakatani T, Inouye M, Mirochnitchenko O. Overexpression of antioxidant enzymes in transgenic mice decreases cellular ploidy during liver regeneration. Exp Cell Res 1997;236:137–146.

[161] Nevzorova YA, Tschaharganeh D, Gassler N et al. Aberrant cell cycle progression and endoreplication in regenerating livers of mice that lack a single E-type cyclin. Gastroenterology 2009;137:691–703

[162] Oberpriller JO, Oberpriller JC. Response of the adult newt ventricle to injury. J Exp Zool 1974;187:249–259.

[163] Ogawa H, Takyu R, Morimoto H et al. Cell proliferation potency is independent of FGF4 signaling in trophoblast stem cells derived from androgenetic embryos. J Reprod Dev 2016;62:51–58.

[164] Oliver TG, Meylan E, Chang GP et al. Caspase-2-mediated cleavage of Mdm2 creates a p53-induced positive feedback loop. Mol Cell 2011;43:57–71.

[165] Olivetti G, Cigola E, Maestri R et al. Aging, cardiac hypertrophy and ischemic cardiomyopathy do not affect the proportion of mononucleated and multinucleated myocytes in the human heart. J Mol Cell Cardiol 1996;28:1463–1477.

[166] Oparil S, Bishop SP, Clubb FJ Jr. Myocardial cell hypertrophy or hyperplasia. Hypertension 1984;6:III38–III43.

[167] Ortica S, Tarantino N, Aulner N et al. The 4 notch receptors play distinct and antagonistic roles in the proliferation and hepatocytic differentiation of liver progenitors. FASEB J 2014;28:603–614.

[168] Ostergaard KH, Baandrup UT, Wang T et al. Left ventricular morphology of the giraffe heart examined by stereological methods. Anat Rec (Hoboken) 2013;296:611–621.

[169] Overturf K, Al-Dhalimy M, Tanguay R et al. Hepatocytes corrected by gene therapy are selected in vivo in a murine model of hereditary tyrosinaemia type I. Nat Genet 1996;12:266–273.

[170] Overturf K, Al-Dhalimy M, Finegold M et al. The repopulation potential of hepatocyte populations differing in size and prior mitotic expansion. Am J Pathol 1999;155:2135–2143.

[171] Panattoni M, Maiorino L, Lukacs A et al. The COP9 signalosome is a repressor of replicative stress responses and polyploidization in the regenerating liver. Hepatology 2014;59:2331–2343.

[172] Pandit SK, Westendorp B, Nantasanti S et al. E2F8 is essential for polyploidization in mammalian cells. Nat Cell Biol 2012;14:1181–1191.

[173] Pascreau G, Churchill ME, Maller JL. Centrosomal localization of cyclins E and A: structural similarities and functional differences. Cell Cycle 2011;10:199–205.

[174] Patel D, Incassati A, Wang N et al. Human papillomavirus type 16 E6 and E7 cause polyploidy in human keratinocytes and up-regulation of G2-M-phase proteins. Cancer Res 2004;64:1299–1306.

[175] Patterson M, Barske L, Van Handel B et al. Frequency of mononuclear diploid cardiomyocytes underlies natural variation in heart regeneration. Nat Genet 2017;49:1346–1353.

[176] Pedone E, Olteanu VA, Marucci L et al. Modeling dynamics and function of bone marrow cells in mouse liver regeneration. Cell Rep 2017;18:107–121.

[177] Perez de Castro I, Aguirre-Portoles C, Fernandez-Miranda G et al. Requirements for Aurora-A in tissue regeneration and tumor development in adult mammals. Cancer Res 2013;73:6804–6815.

[178] Porrello ER, Mahmoud AI, Simpson E et al. Transient regenerative potential of the neonatal mouse heart. Science 2011;331:1078–1080.

[179] Poss KD, Wilson LG, Keating MT. Heart regeneration in zebrafish. Science 2002;298:2188–2190.

[180] Post J, Hoffman J. Further studies on the replication of rat liver cells in vivo. Exp Cell Res 1965;40:333–339.

[181] Puente BN, Kimura W, Muralidhar SA et al. The oxygen-rich postnatal environment induces cardiomyocyte cell-cycle arrest through DNA damage response. Cell 2014;157:565–579.

[182] Rajvanshi P, Liu D, Ott M et al. Fractionation of rat hepatocyte subpopulations with varying metabolic potential, proliferative capacity, and retroviral gene transfer efficiency. Exp Cell Res 1998;244:405–419.

[183] Raulf A, Horder H, Tarnawski L et al. Transgenic systems for unequivocal identification of cardiac myocyte nuclei and analysis of cardiomyocyte cell cycle status. Basic Res Cardiol 2015;110:33.

[184] Reid BJ, Haggitt RC, Rubin CE et al. Barrett’s esophagus. Correlation between flow cytometry and histology in detection of patients at risk for adenocarcinoma. Gastroenterology 1987;93:1–11.

[185] Rengstl B, Newrzela S, Heinrich T et al. Incomplete cytokinesis and re-fusion of small mononucleated Hodgkin cells lead to giant multinucleated Reed-Sternberg cells. Proc Natl Acad Sci U S A 2013;110:9–20734.

[186] Rios AC, Fu NY, Jamieson PR et al. Essential role for a novel population of binucleated mammary epithelial cells in lactation. Nat Commun 2016;7:11400.

[187] Rua S, Comino A, Fruttero A et al. Flow cytometric DNA analysis of cirrhotic liver cells in patients with hepatocellular carcinoma can provide a new prognostic factor. Cancer 1996;78:1195–1202.

[188] Saeter G, Lee CZ, Schwarze PE et al. Changes in ploidy distributions in human liver carcinogenesis. J Natl Cancer Inst 1988;80:1480–1485.

[189] Sanges D, Romo N, Simonte G et al. Wnt/beta-catenin signaling triggers neuron reprogramming and regeneration in the mouse retina. Cell Rep 2013;4:271–286.

[190] Sanz N, Diez-Fernandez C, Fernandez-Simon L et al. Relationship between antioxidant systems, intracellular thiols and DNA ploidy in liver of rats during experimental cirrhogenesis. Carcinogenesis 1995;16:1585–1593.

[191] Schoenfelder KP, Fox DT. The expanding implications of polyploidy. J Cell Biol 2015;209:485–491.

[192] Senyo SE, Steinhauser ML, Pizzimenti CL et al. Mammalian heart renewal by pre-existing cardiomyocytes. Nature 2013;493:433–436.

[193] Shapiro SD, Ranjan AK, Kawase Y et al. Cyclin A2 induces cardiac regeneration after myocardial infarction through cytokinesis of adult cardiomyocytes. Sci Transl Med 2014;6:224ra227.

[194] Sher N, Von Stetina JR, Bell GW et al. Fundamental differences in endoreplication in mammals and Drosophila revealed by analysis of endocycling and endomitotic cells. Proc Natl Acad Sci U S A 2013;110:9368–9373.

[195] Sigal SH, Gupta S, Gebhard DF Jr. et al. Evidence for a terminal differentiation process in the rat liver. Differentiation 1995;59:35–42.

[196] Sigal SH, Rajvanshi P, Gorla GR et al. Partial hepatectomy-induced polyploidy attenuates hepatocyte replication and activates cell aging events. Am J Physiol 1999;276:G1260–G1272.

[197] Sladky VC, Villunger A. Uncovering the PIDDosome and caspase-2 as regulators of organogenesis and cellular differentiation. Cell Death Differ 2020;27:2037–2047.

[198] Sladky VC, Knapp K, Soratroi C et al. E2F-family members engage the PIDDosome to limit hepatocyte ploidy in liver development and regeneration. Dev Cell 2020a;52:335–349

[199] Sladky VC, Knapp K, Szabo TG et al. PIDDosome-induced p53-dependent ploidy restriction facilitates hepatocarcinogenesis. EMBO Rep 2020b;21:e50893.

[200] Sladky VC, Eichin F, Reiberger T et al. Polyploidy control in hepatic health and disease. J Hepatol 2021;75:1177–1191.

[201] Sladky VC, Akbari H, Tapias-Gomez D et al. Centriole signaling restricts hepatocyte ploidy to maintain liver integrity. Genes Dev 2022;36:843–856.

[202] Smith GH, Medina D. A morphologically distinct candidate for an epithelial stem cell in mouse mammary gland. J Cell Sci 1988;90:173–183.

[203] Smith GH, Vonderhaar BK. Functional differentiation in mouse mammary gland epithelium is attained through DNA synthesis, inconsequent of mitosis. Dev Biol 1981;88:167–179.

[204] Soonpaa MH, Kim KK, Pajak L et al. Cardiomyocyte DNA synthesis and binucleation during murine development. Am J Physiol 1996;271:H2183–H2189.

[205] Soonpaa MH, Koh GY, Pajak L et al. Cyclin D1 overexpression promotes cardiomyocyte DNA synthesis and multinucleation in transgenic mice. J Clin Invest 1997;99:2644–2654.

[206] Starnes AC, Huisingh C, McGwin G Jr. et al. Multi-nucleate retinal pigment epithelium cells of the human macula exhibit a characteristic and highly specific distribution. Vis Neurosci 2016;33:e001.

[207] Steigemann P, Wurzenberger C, Schmitz MH et al. Aurora B-mediated abscission checkpoint protects against tetraploidization. Cell 2009;136:473–484.

[208] Stopp S, Grundl M, Fackler M et al. Deletion of Gas2l3 in mice leads to specific defects in cardiomyocyte cytokinesis during development. Proc Natl Acad Sci U S A 2017;114:8029–8034.

[209] Tanami S, Ben-Moshe S, Elkayam A et al. Dynamic zonation of liver polyploidy. Cell Tissue Res 2017;368:405–410.

[210] Tane S, Ikenishi A, Okayama H et al. CDK inhibitors, p21(Cip1) and p27(Kip1), participate in cell cycle exit of mammalian cardiomyocytes. Biochem Biophys Res Commun 2014;443:1105–1109.

[211] Tinel A, Tschopp J. The PIDDosome, a protein complex implicated in activation of caspase-2 in response to genotoxic stress. Science 2004;304:843–846.

[212] Tormos AM, Arduini A, Talens-Visconti R et al. Liver-specific p38alpha deficiency causes reduced cell growth and cytokinesis failure during chronic biliary cirrhosis in mice. Hepatology 2013;57:1950–1961.

[213] Tormos AM, Rius-Perez S, Jorques M et al. p38alpha regulates actin cytoskeleton and cytokinesis in hepatocytes during development and aging. PLoS One 2017;12:e0171738.

[214] Torres S, Diaz BP, Cabrera JJ et al. Thyroid hormone regulation of rat hepatocyte proliferation and polyploidization. Am J Physiol 1999;276:G155–G163.

[215] Toyoda H, Bregerie O, Vallet A et al. Changes to hepatocyte ploidy and binuclearity profiles during human chronic viral hepatitis. Gut 2005;54:297–302.

[216] Toyoda H, Kumada T, Bregerie O et al. Conserved balance of hepatocyte nuclear DNA content in mononuclear and binuclear hepatocyte populations during the course of chronic viral hepatitis. World J Gastroenterol 2006;12:4546–4548.

[217] Troadec MB, Courselaud B, Detivaud L et al. Iron overload promotes Cyclin D1 expression and alters cell cycle in mouse hepatocytes. J Hepatol 2006;44:391–399.

[218] Turker MS, Schwartz JL, Jordan R et al. Persistence of chromatid aberrations in the cells of solid mouse tissues exposed to 137Cs gamma radiation. Radiat Res 2004;162:357–364.

[219] Ullah Z, Kohn MJ, Yagi R et al. Differentiation of trophoblast stem cells into giant cells is triggered by p57/Kip2 inhibition of CDK1 activity. Genes Dev 2008;22:3024–3036.

[220] Unhavaithaya Y, Orr-Weaver TL. Polyploidization of glia in neural development links tissue growth to blood-brain barrier integrity. Genes Dev 2012;26:31–36.

[221] Vinogradov AE, Anatskaya OV, Kudryavtsev BN. Relationship of hepatocyte ploidy levels with body size and growth rate in mammals. Genome 2001;44:350–360.

[222] Vliegen HW, van der Laarse A, Cornelisse CJ et al. Myocardial changes in pressure overload-induced left ventricular hypertrophy. A study on tissue composition, polyploidization and multinucleation. Eur Heart J 1991;12:488–494.

[223] Vliegen HW, Eulderink F, Bruschke AV et al. Polyploidy of myocyte nuclei in pressure overloaded human hearts: a flow cytometric study in left and right ventricular myocardium. Am J Cardiovasc Pathol 1995;5:27–31.

[224] Vonderhaar BK, Smith GH, Pauley RJ et al. Difference between mammary epithelial cells from mature virgin and primiparous mice. Cancer Res 1978;38:4059–4065.

[225] Von Stetina JR, Frawley LE, Unhavaithaya Y et al. Variant cell cycles regulated by Notch signaling control cell size and ensure a functional blood-brain barrier. Development 2018;145.

[226] Vujic A, Lerchenmuller C, Wu TD et al. Exercise induces new cardiomyocyte generation in the adult mammalian heart. Nat Commun 2018;9:1659.

[227] Wang MJ, Chen F, Li JX et al. Reversal of hepatocyte senescence after continuous in vivo cell proliferation. Hepatology 2014;60:349–361.

[228] Wang B, Zhao L, Fish M et al. Self-renewing diploid Axin2(+) cells fuel homeostatic renewal of the liver. Nature 2015;524:180–185.

[229] Wang WE, Li L, Xia X et al. Dedifferentiation, proliferation, and redifferentiation of adult mammalian cardiomyocytes after ischemic injury. Circulation 2017;136:834–848.

[230] Webber EM, Godowski PJ, Fausto N. In vivo response of hepatocytes to growth factors requires an initial priming stimulus. Hepatology 1994;19:489–497.

[231] Webber EM, Bruix J, Pierce RH et al. Tumor necrosis factor primes hepatocytes for DNA replication in the rat. Hepatology 1998;28:1226–1234.

[232] Weglarz TC, Degen JL, Sandgren EP. Hepatocyte transplantation into diseased mouse liver. Kinetics of parenchymal repopulation and identification of the proliferative capacity of tetraploid and octaploid hepatocytes. Am J Pathol 2000;157:1963–1974.

[233] Wen Q, Goldenson B, Silver SJ et al. Identification of regulators of polyploidization presents therapeutic targets for treatment of AMKL. Cell 2012;150:575–589.

[234] Werle K, Chen J, Xu HG et al. Liver kinase B1 regulates the centrosome via PLK1. Cell Death Dis 2014;5:e1157.

[235] Wheatley DN. Binucleation in mammalian liver. Studies on the control of cytokinesis in vivo. Exp Cell Res 1972;74:455–465.

[236] White JW, Swartz FJ, Swartz AF. Excess glucose intake induces accelerated beta-cell polyploidization in normal mice: a possible deleterious effect. J Nutr 1985;115:271–278.

[237] Wilkinson PD, Alencastro F, Delgado ER et al. Polyploid hepatocytes facilitate adaptation and regeneration to chronic liver injury. Am J Pathol 2019a;189:1241–1255.

[238] Wilkinson PD, Delgado ER, Alencastro F et al. The polyploid state restricts hepatocyte proliferation and liver regeneration in mice. Hepatology 2019b;69:1242–1258.

[239] Willenbring H, Bailey AS, Foster M et al. Myelomonocytic cells are sufficient for therapeutic cell fusion in liver. Nat Med 2004;10:744–748.

[240] Wills AA, Holdway JE, Major RJ et al. Regulated addition of new myocardial and epicardial cells fosters homeostatic cardiac growth and maintenance in adult zebrafish. Development 2008;135:183–192.

[241] Wu H, Wade M, Krall L et al. Targeted in vivo expression of the cyclin- dependent kinase inhibitor p21 halts hepatocyte cell-cycle progression, postnatal liver development and regeneration. Genes Dev 1996;10:245–260.

[242] Xiao G, Mao S, Baumgarten G et al. Inducible activation of c-Myc in adult myocardium in vivo provokes cardiac myocyte hypertrophy and reactivation of DNA synthesis. Circ Res 2001;89:1122–1129.

[243] Yanger K, Knigin D, Zong Y et al. Adult hepatocytes are generated by self-duplication rather than stem cell differentiation. Cell Stem Cell 2014;15:340–349.

[244] Ye L, Qiu L, Zhang H et al. Cardiomyocytes in young infants with congenital heart disease: a three-month window of proliferation. Sci Rep 2016;6:23188.

[245] Yoshida S, Bartolini S, Pellman D. Mechanisms for concentrating Rho1 during cytokinesis. Genes Dev 2009;23:810–823.

[246] Zajicek G, Oren R, Weinreb M Jr. The streaming liver. Liver 1985;5:293–300.

[247] Zanet J, Freije A, Ruiz M et al. A mitosis block links active cell cycle with human epidermal differentiation and results in endoreplication. PLoS One 2010;5:e15701.

[248] Zebrowski DC, Vergarajauregui S, Wu CC et al. Developmental alterations in centrosome integrity contribute to the post-mitotic state of mammalian cardiomyocytes. Elife 2015;4.

[249] Zhang S, Zhou K, Luo X et al. The polyploid state plays a tumor-suppressive role in the liver. Dev Cell 2018a;44:447–459

[250] Zhang S, Nguyen LH, Zhou K et al. Knockdown of anillin actin binding protein blocks cytokinesis in hepatocytes and reduces liver tumor development in mice without affecting regeneration. Gastroenterology 2018b;154:1421–1434.

[251] Zhong L, Georgia S, Tschen SI et al. Essential role of Skp2-mediated p27 degradation in growth and adaptive expansion of pancreatic beta cells. J Clin Invest 2007;117:2869–2876.

[252] Zhou J, Ahmad F, Parikh S et al. Loss of adult cardiac myocyte GSK-3 leads to mitotic catastrophe resulting in fatal dilated cardiomyopathy. Circ Res 2016;118:1208–1222.

[253] Zielke N, Querings S, Rottig C et al. The anaphase-promoting complex/ cyclosome (APC/C) is required for rereplication control in endoreplication cycles. Genes Dev 2008;22:1690–1703.

[254] Zulbahar S, Sieglitz F, Kottmeier R et al. Differential expression of Obek controls ploidy in the Drosophila blood-brain barrier. Development 2018;145.

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