Polyploidization of liver cells

  • Séverine Celton-Morizur
  • Chantal DesdouetsEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 676)


Eukaryotic organisms usually contain a diploid complement of chromosomes. However, there are a number of exceptions. Organisms containing an increase in DNA content by whole number multiples of the entire set of chromosomes are defined as polyploid. Cells that contain more than two sets of chromosomes were first observed in plants about a century ago and it is now recognized that polyploidy cells form in many eukaryotes under a wide variety of circumstance. Although it is less common in mammals, some tissues, including the liver, show a high percentage of polyploid cells. Thus, during postnatal growth, the liver parenchyma undergoes dramatic changes characterized by gradual polyploidization during which hepatocytes of several ploidy classes emerge as a result of modified cell-division cycles. This process generates the successive appearance of tetraploid and octoploid cell classes with one or two nuclei (mononucleated or binucleated). Liver cells polyploidy is generally considered to indicate terminal differentiation and senescence and to lead both to the progressive loss of cell pluripotency and a markedly decreased replication capacity. In adults, liver polyploidization is differentially regulated upon loss of liver mass and liver damage. Interestingly, partial hepatectomy induces marked cell proliferation followed by an increase in liver ploidy. In contrast, during hepatocarcinoma (HCC), growth shifts to a nonpolyploidizing pattern and expansion of the diploid hepatocytes population is observed in neoplastic nodules. Here we review the current state of understanding about how polyploidization is regulated during normal and pathological liver growth and detail by which mechanisms hepatocytes become polyploid.


Liver Regeneration Partial Hepatectomy Liver Growth Ploidy Class Extra Centrosome 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Michalopoulos GK, DeFrances MC. Liver regeneration. Science 1997; 276:60–6.PubMedCrossRefGoogle Scholar
  2. 2.
    Saxema R, Zucker SD, Crawford JM. Chapter 1. In: Zakim DZ, and Boyer TD, eds. Hepathology: a textbook of liver disease. Philadelphia: W.B. Saunders Company, 2003:43–58.Google Scholar
  3. 3.
    Taub R. Liver regeneration: from myth to mechanism. Nat Rev Mol Cell Biol 2004; 5(10):836–47.PubMedCrossRefGoogle Scholar
  4. 4.
    Jungermann K, Kietzmann T. Zonation of parenchymal and nonparenchymal metabolism in liver. Annu Rev Nutr 1996; 16:179–203.PubMedCrossRefGoogle Scholar
  5. 5.
    Alfert M, Geswind I. The development of polysomaty in rat liver. Exp Cell Res 1958; 15:230–5.PubMedCrossRefGoogle Scholar
  6. 6.
    Brodsky WY, Uryvaeva IV. Cell polyploidy: its relation to tissue growth and function. Int Rev Cytol 1977; 50:275–332.PubMedCrossRefGoogle Scholar
  7. 7.
    Carriere R. Polyploid cell reproduction in normal adult rat liver. Exp Cell Res 1967; 46:533–40.PubMedCrossRefGoogle Scholar
  8. 8.
    Epstein CJ. Cell size, nuclear content and the development of polyploidy in the mammalian liver. Proc Natl Acad Sci USA 1967; 57:327–34.PubMedCrossRefGoogle Scholar
  9. 9.
    Gerlyng P, Abyholm A, Grotmol T et al. Binucleation and polyploidization patterns in developmental and regenerative rat liver growth. Cell Prolif 1993; 26(6):557–65.PubMedCrossRefGoogle Scholar
  10. 10.
    Nadal C, Zajdela F. [Hepatic polyploidy in the rat. IV. Experimental changes in the nucleolar volume of liver cells and their mechanisms of regulation]. Exp Cell Res 1967; 48(3):518–28.PubMedCrossRefGoogle Scholar
  11. 11.
    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(6):387–93.CrossRefGoogle Scholar
  12. 12.
    Severin E, Meier EM, Williers R. Flow cytometric analysis of mouse hepatocyte ploidy. The development of polyploidy pattern in four mice strains with differents life spans. Cell Tissue Res 1984; 238:649–52.PubMedCrossRefGoogle Scholar
  13. 13.
    Schmucker DL. Hepatocyte fine structure during maturation and senescence. J Electron Microsc Tech 1990; 14(2):106–25.PubMedCrossRefGoogle Scholar
  14. 14.
    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(5 Pt 1):G1260–72.PubMedGoogle Scholar
  15. 15.
    Gerlyng P, Grotmol T, Erikstein B et al. Reduced proliferative activity of polyploid cells in primary hepatocellular carcinoma. Carcinogenesis 1992; 13:1795–801.PubMedCrossRefGoogle Scholar
  16. 16.
    Mossin L, Blankson H, Huitfeldt H et al. Ploidy-dependent growth and binucleation in cultured rat hepatocytes. Exp Cell Res 1994; 214(2):551–60.PubMedCrossRefGoogle Scholar
  17. 17.
    Germain L, Blouin MJ, Marceau N. Biliary epithelial and hepatocytic cell lineage relationships in embryonic rat liver as determined by the differential expression of cytokeratins, alpha-fetoprotein, albumin and cell surface-exposed components. Cancer Res 1988; 48(17):4909–18.PubMedGoogle Scholar
  18. 18.
    Shiojiri N, Lemire JM, Fausto N. Cell lineages and oval cell progenitors in rat liver development. Cancer Res 1991; 51(10):2611–20.PubMedGoogle Scholar
  19. 19.
    Viola-Magni MP. Synthesis and turnover of DNA in hepatocytes of neonatal rats. J Microsc 1972; 96(2):191–203.PubMedCrossRefGoogle Scholar
  20. 20.
    Nadal C, Zajdela F. [Somatic polyploid cells in rat liver. I. The role of binuclear cells in the formation of the polyploid cells]. Exp Cell Res 1966; 42(1):99–]ReferencesPubMedCrossRefGoogle Scholar
  21. 21.
    An CS, Petrovic LM, Reyter I et al. The application of image analysis and neural network technology to the study of large-cell liver-cell dysplasia and hepatocellular carcinoma. Hepatology 1997; 26(5):1224–31.PubMedCrossRefGoogle Scholar
  22. 22.
    Yin L, Ghebranious N, Chakraborty S et al. Control of mouse hepatocyte proliferation and ploidy by p53 and p53ser246 mutation in vivo. Hepatology 1998; 27(1):73–80.PubMedCrossRefGoogle Scholar
  23. 23.
    Sigal SH, Gupta S, Gebhard DF et al. Evidence for a terminal differentiation process in the rat liver. Differentiation 1995; 59(1):35–42.PubMedCrossRefGoogle Scholar
  24. 24.
    Hasmall SC, Roberts RA. Hepatic ploidy, nuclearity and distribution of DNA synthesis: a comparison of nongenotoxic hepatocarcinogens with noncarcinogenic liver mitogens. Toxicol Appl Pharmacol 1997; 144(2):287–93.PubMedCrossRefGoogle Scholar
  25. 25.
    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(2):138–44.PubMedCrossRefGoogle Scholar
  26. 26.
    Guidotti JE, Bregerie O, Robert A et al. Liver cell polyploidization: a pivotal role for binuclear hepatocytes. J Biol Chem 2003 23; 278(21):19095–101.PubMedCrossRefGoogle Scholar
  27. 27.
    Toyoda H, Bregerie O, Vallet A et al. Changes to hepatocyte ploidy and binuclearity profiles during human chronic viral hepatitis. Gut 2005; 54(2):297–302.PubMedCrossRefGoogle Scholar
  28. 28.
    Anatskaya OV, Vinogradov AE, Kudryavtsev BN. Hepatocyte polyploidy and metabolism/life-history traits: hypotheses testing. J Theor Biol 1994 21; 168(2):191–9.PubMedCrossRefGoogle Scholar
  29. 29.
    Wheatley DN. Binucleation in mammalian liver. Studies on the control of cytokinesis in vivo. Exp Cell Res 1972; 74(2):455–65.PubMedCrossRefGoogle Scholar
  30. 30.
    Carriere R. The growth of liver-parenchymal nuclei and its endocrine regulation. Inter Rev Cytology 1969; 25:201–78.CrossRefGoogle Scholar
  31. 31.
    Mac Donald WE. lifespan of liver cells. Arch Internal Med 1961; 107:335–43.CrossRefGoogle Scholar
  32. 32.
    Deschenes J, Valet JP, Marceau N. The relationship between cell volume, ploidy and functional activity in differentiating hepatocytes. Cell Biophys 1981; 3(4):321–34.PubMedGoogle Scholar
  33. 33.
    Watanabe T, Tanaka Y. Age-related alterations in the size of human hepatocytes. A study of mononuclear and binucleate cells. Virchows Arch B Cell Pathol Incl Mol Pathol 1982; 39(1):9–20.PubMedCrossRefGoogle Scholar
  34. 34.
    Mortimer RK. Radiobiological and genetic studies on a polyploid series (haploid to hexaploid) of Saccharomyces cerevisiae. Radiat Res 1958; 9:312–26.PubMedCrossRefGoogle Scholar
  35. 35.
    Asahina K, Shiokawa M, Ueki T et al. Multiplicative mononuclear small hepatocytes in adult rat liver: their isolation as a homogeneous population and localization to periportal zone. Biochem Biophys Res Commun 2006; 342(4):1160–7.PubMedCrossRefGoogle Scholar
  36. 36.
    Gandillet A, Alexandre E, Holl V et al. Hepatocyte ploidy in normal young rat. Comp Biochem Physiol A Mol Integr Physiol 2003; 134(3):665–73.PubMedCrossRefGoogle Scholar
  37. 37.
    Margall-Ducos G, Celton-Morizur S, Couton D et al. Liver Tetraploidization is Controlled by a New Process of Incomplete Cytokinesis. Journal of Cell Science 2007; 120:3633–3639.PubMedCrossRefGoogle Scholar
  38. 38.
    Enesco HE, Shimokawa I, Yu BP. Effect of dietary restriction and aging on polyploidy in rat liver. Mech Ageing Dev 1991; 59(1–2):69–78.PubMedCrossRefGoogle Scholar
  39. 39.
    Enesco HE, Samborsky J. Liver polyploidy: influence of age and of dietary restriction. Exp Gerontol 1983; 18(1):79–87.PubMedCrossRefGoogle Scholar
  40. 40.
    Geschwind I, Alfert M, Schooley C. The effect of thyroxine and growth hormone on liver polyploidy. Biol Bull 1960; 118:66–9.CrossRefGoogle Scholar
  41. 41.
    Nadal C, Zajdela F. [Polyploidy in the rat liver. II. The role of the hypophysis and protein deficiency]. Exp Cell Res 1966; 42(1):117–29.PubMedCrossRefGoogle Scholar
  42. 42.
    Swartz FJ, Ford JD Jr. Effect of thyroidectomy on development of polyploid nuclei in rat liver. Proc Soc Exp Biol Med 1960; 104:756–9.PubMedGoogle Scholar
  43. 43.
    Swartz FJ, Sams BF. Polyploidization of rat liver following sex hormone administration to castrate and intact rats. Anat Rec 1961; 141:219–25.PubMedCrossRefGoogle Scholar
  44. 44.
    Swartz FJ, Sams BF, Barton AG. Polyploidization of rat liver following castration of males and females. Exp Cell Res 1960; 438–444.Google Scholar
  45. 45.
    Mendecki J, Dillmann WH, Wolley RC et al. Effect of thyroid hormone on the ploidy of rat liver nuclei as determined by flow-cytometry. Proc Soc Exp Biol Med 1978; 158(1):63–M.PubMedGoogle Scholar
  46. 46.
    Torres S, Diaz BP, Cabrera JJ et al. Thyroid hormone regulation of rat hepatocyte proliferation and polyploidization. Am J Physiol 1999; 276(1 Pt 1):G155–63.PubMedGoogle Scholar
  47. 47.
    Edgar BA, Orr-Weaver TL. Endoreplication cell cycles: more for less. Cell 2001; 105(3):297–306.PubMedCrossRefGoogle Scholar
  48. 48.
    Cebolla A, Vinardell JM, Kiss E et al. The mitotic inhibitor ccs52 is required for endoreduplication and ploidy-dependent cell enlargement in plants. EMBO J 1999 16; 18(16):4476–84.PubMedCrossRefGoogle Scholar
  49. 49.
    Kondorosi E, Roudier F, Gendreau E. Plant cell-size control: growing by ploidy? Curr Opin Plant Biol 2000; 3(6):488–92.PubMedCrossRefGoogle Scholar
  50. 50.
    Ravid K, Lu J, Zimmet JM et al. Roads to polyploidy: the megakaryocyte example. J Cell Physiol 2002; 190(1):7–20.PubMedCrossRefGoogle Scholar
  51. 51.
    Minamishima YA, Nakayama K. Recovery of liver mass without proliferation of hepatocytes after partial hepatectomy in Skp2-deficient mice. Cancer Res 2002; 62(4):995–9.PubMedGoogle Scholar
  52. 52.
    Nunez F, Chipchase MD, Clarke AR et al. Nucleotide excision repair gene (ERCC1) deficiency causes G(2) arrest in hepatocytes and a reduction in liver binucleation: the role of p53 and p21. FASEB J 2000; 14(9):1073–82.PubMedGoogle Scholar
  53. 53.
    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 and Dev 1996; 10:245–60.PubMedCrossRefGoogle Scholar
  54. 54.
    Taylor MV. Muscle differentiation: how two cells become one. Curr Biol 2002; 12(6):R224–8.PubMedCrossRefGoogle Scholar
  55. 55.
    Vignery A. Osteoclasts and giant cells: macrophage-macrophage fusion mechanism. Int J Exp Pathol 2000; 81(5):291–304.PubMedCrossRefGoogle Scholar
  56. 56.
    Gomez-Lechon MJ, Barbera E, Gil R et al. Evolutive changes of ploidy and polynucleation in adult rat hepatocytes in culture. Cell Mol Biol 1981; 27(6):695–701.Google Scholar
  57. 57.
    Hernandez LD, Hoffman LR, Wolfsberg TG et al. Virus-cell and cell-cell fusion. Annu Rev Cell Dev Biol 1996; 12:627–61.PubMedCrossRefGoogle Scholar
  58. 58.
    Eggert US, Mitchison TJ, Field CM. Animal cytokinesis: from parts list to mechanisms. Annu Rev Biochem 2006; 75:543–66.PubMedCrossRefGoogle Scholar
  59. 59.
    Storchova Z, Pellman D. From polyploidy to aneuploidy, genome instability and cancer. Nat Rev Mol Cell Biol 2004; 5(1):45–54.PubMedCrossRefGoogle Scholar
  60. 60.
    Gustafson LM, Gleich LL, Fukasawa K et al. Centrosome hyperamplification in head and neck squamous cell carcinoma: a potential phenotypic marker of tumor aggressiveness. Laryngoscope 2000; 110(11):1798–801.PubMedCrossRefGoogle Scholar
  61. 61.
    Lingle WL, Lutz WH, Ingle JN et al. Centrosome hypertrophy in human breast tumors: implications for genomic stability and cell polarity. Proc Natl Acad Sci USA 1998; 95(6):2950–5.PubMedCrossRefGoogle Scholar
  62. 62.
    Lingle WL, Salisbury JL. Altered centrosome structure is associated with abnormal mitoses in human breast tumors. Am J Pathol 1999; 155(6):1941–51.PubMedCrossRefGoogle Scholar
  63. 63.
    Pihan GA, Purohit A, Wallace J et al. Centrosome defects and genetic instability in malignant tumors. Cancer Res 1998; 58(17):3974–85.PubMedGoogle Scholar
  64. 64.
    Pihan GA, Purohit A, Wallace J et al. Centrosome defects can account for cellular and genetic changes that characterize prostate cancer progression. Cancer Res 2001; 61(5):2212–9.PubMedGoogle Scholar
  65. 65.
    Weber RG, Bridger JM, Benner A et al. Centrosome amplification as a possible mechanism for numerical chromosome aberrations in cerebral primitive neuroectodermal tumors with TP53 mutations. Cytogenet Cell Genet 1998; 83(3–4):266–9.PubMedCrossRefGoogle Scholar
  66. 66.
    Fausto N, Campbell JS, Riehle KJ. Liver regeneration. Hepatology 2006; 43(2 Suppl 1):S45–53.PubMedCrossRefGoogle Scholar
  67. 67.
    Dimri GP, Lee X, Basile G et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci USA 1995; 92(20):9363–7.PubMedCrossRefGoogle Scholar
  68. 68.
    Melchiorri C, Chieco P, Zedda AI et al. Ploidy and nuclearity of rat hepatocytes after compensatory regeneration or mitogen-induced liver growth. Carcinogenesis 1993; 14(9):1825–30.PubMedCrossRefGoogle Scholar
  69. 69.
    Martin NC, McGregor AH, Sansom N et al. Phenobarbitone-induced ploidy changes in liver occur independently of p53. Toxicol Lett 2001; 119(2):109–15.PubMedCrossRefGoogle Scholar
  70. 70.
    Miller RT, Shah RS, Cattley RC et al. The peroxisome proliferations WY-14,643 and methylclofenapate induce hepatocyte ploidy alterations and ploidy-specific DNA synthesis in F344 rats. Toxicol Appl Pharmacol 1996; 138(2):317–23.PubMedCrossRefGoogle Scholar
  71. 71.
    Muramatsu Y, Yamada T, Miura M et al. Wilson’s disease gene is homologous to hts causing abnormal copper transport in Long-Evans cinnamon rats. Gastroenterology 1994; 107(4):1189–92.PubMedGoogle Scholar
  72. 72.
    Terada K, Sugiyama T. The Long-Evans Cinnamon rat: an animal model for Wilson’s disease. Pediatr Int 1999; 41(4):414–8.PubMedCrossRefGoogle Scholar
  73. 73.
    Schilsky ML, Stockert RJ, Sternlieb I. Pleiotropic effect of LEC mutation: a rodent model of Wilson’s disease. Am J Physiol 1994; 266(5 Pt 1):G907–13.PubMedGoogle Scholar
  74. 74.
    Kato J, Kohgo Y, Sugawara N et al. Abnormal hepatic iron accumulation in LEC rats. Jpn J Cancer Res 1993; 84(3):219–22.PubMedCrossRefGoogle Scholar
  75. 75.
    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(1–2):129–36.PubMedGoogle Scholar
  76. 76.
    Yamada T, Sogawa K, Kim JK et al. Increased polyploidy, delayed mitosis and reduced protein phosphatase-1 activity associated with excess copper in the Long Evans Cinnamon rat. Res Commun Mol Pathol Pharmacol 1998; 99(3):283–304.PubMedGoogle Scholar
  77. 77.
    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(4):719–27.PubMedCrossRefGoogle Scholar
  78. 78.
    Gorla GR, Malhi H, Gupta S. Polyploidy associated with oxidative injury attenuates proliferative potential of cells. J Cell Sci 2001; 114(Pt 16):2943–51.PubMedGoogle Scholar
  79. 79.
    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 USA 2002; 99(20):13114–9.PubMedCrossRefGoogle Scholar
  80. 80.
    Nakatani T, Inouye M, Mirochnitchenko O. Overexpression of antioxidant enzymes in transgenic mice decreases cellular ploidy during liver regeneration. Exp Cell Res 1997; 236(1):137–46.PubMedCrossRefGoogle Scholar
  81. 81.
    Seglen PO. DNA ploidy and autophagic protein degradation as determinants of hepatocellular growth and survival. Cell Biology and Toxicology 1997; 13:301–15.PubMedCrossRefGoogle Scholar
  82. 82.
    Saeter G, Schwarze PE, Nesland JM et al. The polyploidizing growth pattern of normal rat liver is replaced by divisional, diploid growth in hepatocellular nodules and carcinomas. Carcinogenesis 1988; 9:939–45.PubMedCrossRefGoogle Scholar
  83. 83.
    Saeter G, Schwarze PE, Nesland JM et al. Diploid nature of hepatocellular tumours developing from transplanted preneoplastic liver cells. Br J Cancer 1989; 59(2):198–205.PubMedCrossRefGoogle Scholar
  84. 84.
    Schwarze PE, Pettersen EO, Shoaib MC et al. Emergence of a population of small, diploid hepatocytes during hepatocarcinogenesis. Carcinogenesis 1984; 5:1267–75.PubMedCrossRefGoogle Scholar
  85. 85.
    Schwarze PE, Pettersen EO, Tolleshaug H et al. Isolation of carcinogen-induced diploid rat hepatocytes by centrifugal elutriation. Cancer Res 1986; 46(9):4732–7.PubMedGoogle Scholar
  86. 86.
    Schwarze PE, Saeter G, Armstrong D et al. Diploid growth pattern of hepatocellular tumours induced by various carcinogenesis treatments. Carcinogenesis 1991; 12:325–7.PubMedCrossRefGoogle Scholar
  87. 87.
    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 15; 73(2):281–8.PubMedCrossRefGoogle Scholar
  88. 88.
    Melchiorri C, Bolondi L, Chieco P et al. Diagnostic and prognostic value of DNA ploidy and cell nuclearity in ultrasound-guided liver biopsies. Cancer 1994; 74(6):1713–9.PubMedCrossRefGoogle Scholar
  89. 89.
    Hoso M, Nakanuma Y. Cytophotometric DNA analysis of adenomatous hyperplasia in cirrhotic livers. Virchows Arch A Pathol Anat Histopathol 1991; 418(5):401–4.PubMedCrossRefGoogle Scholar

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© Landes Bioscience and Springer Science+Business Media 2010

Authors and Affiliations

  1. 1.Institut CochinUniversite Paris Descartes, CNRS (UNR 8104) Inserm U567 Department of Genetic and DevelopmentParisFrance

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