Mini review
Polyploidy and liver proliferation

https://doi.org/10.1016/j.clinre.2011.05.011Get rights and content

Summary

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 polyploid cells form in many eukaryotes under a wide variety of circumstances. Although it is less common in mammals, some tissues, including the liver, show a high percentage of polyploid cells. Thus, during post-natal 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. Liver cell polyploidy is generally considered to indicate terminal differentiation and senescence and to both lead to a progressive loss of cell pluripotency and to a markedly decreased replication capacity. In adults, liver polyploidization is differentially regulated upon loss of liver mass and liver damage. 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.

Section snippets

Abbreviations

    SAC

    spindle assembly checkpoint

    APC

    adenomatous polyposis coliAFM

    PH

    partial hepatectomy

    LEC

    long Evans Cinnamon rats

    WD

    Wilson's disease

Mechanisms generating polyploid cells

One fascinating question is how diploid organisms develop polyploid cells. In a physiological or pathological state, polyploid cells can arise by any of at least five main mechanisms: cell fusion, endoreplication, endomitosis, mitotic slippage and cytokinesis failure (Fig. 1). Cell fusions are important in several physiological processes, including fertilization, development (osteoclasts) and tissue repair (skeletal muscle cells) [9], [10]. Infection with many viruses can also induce cell

Polyploidy and liver growth

Hepatic development is an extended process that continues through early post-natal life. In rat liver, through E14, most hepatoblasts are bipotent with the ability to differentiate into hepatocytes or into biliary cells; however, by E15 most hepatoblasts are committed to the hepatocyte lineage [23], [24]. During the remaining period of gestation and the first four post-natal weeks, hepatoblasts acquire functions of differentiated hepatocytes. In parallel with this process, there is a

Polyploidy in regenerating liver and during pathological states

The adult liver retains a high proliferative capacity. It responds to tissue injuries such as PH, toxin and drug-induced liver disease as well as administration of specific growth factor by priming quiescent hepatocytes [42]. During liver regeneration, after PH, quiescent hepatocytes undergo one or two rounds of replication to restore the liver mass by a process of compensatory hyperplasia. Many studies have shown that during this process hepatic polyploidy is modified [2], [43], [44], [45],

Conclusion and perspectives

Although hepatic polyploidisation has been shown to be associated with physiologic and pathologic events, our understanding of the consequences for hepatocytes is quite limited. Various possibilities can be suggested: (i) polyploidy may protect hepatocytes from genotoxic damage by increasing their gene copy number; this might be especially important for the liver that has a primary function in metabolizing and eliminating toxic compounds. (ii) The polyploidy process may be link to energy

Disclosure of interest

The authors declare that they have no conflicts of interest concerning this article.

Acknowledgements

We thank the editor for inviting this mini review. G. Gentric is a recipient of DIM RĆ©gion Ile de France ā€œCardio-vasculaire DiabĆØte ObĆ©sitĆ©ā€. This study was supported by grants from Institut National de la SantĆ© et de la Recherche MĆ©dicale (Inserm), ANR-FORM-090601-01-01, by INCa-CHC (2009-1-CHC-03-Inserm).

References (65)

  • S.P. Otto

    The evolutionary consequences of polyploidy

    Cell

    (2007)
  • H. Raslova et al.

    Blood

    (2007)
  • O.V. Anatskaya et al.

    Genome multiplication as adaptation to tissue survival: evidence from gene expression in mammalian heart and liver

    Genomics

    (2007)
  • S.P. Otto et al.

    Polyploid incidence and evolution

    Annu Rev Genet

    (2000)
  • W.Y. Brodsky et al.

    Cell polyploidy: it relation to tissue growth and function

    Int Rev Cytol

    (1997)
  • S. Gupta

    Hepatic polyploidy and liver growth control

    Semin Cancer Biol

    (2000)
  • F.L. Van der Heijden et al.

    Polyploidy in the human myometrium

    Z Mikrosk Anat Forsch

    (1975)
  • M.L. Hixon et al.

    Akt1/PKB upregulation leads to vascular smooth muscle cell hypertrophy and polyploidization

    J Clin Invest

    (2000)
  • H.W. Vliegen 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)
  • Z. Storchova et al.

    The consequences of tetraploidy and aneuploidy

    J Cell Sci

    (2008)
  • M.V. Taylor

    Muscle differentiation: how two cells become one

    Curr Biol

    (2000)
  • A. Vignery

    Macrophage fusion: molecular mechanisms

    Methods Mol Biol

    (2008)
  • D. Duelli et al.

    Cell-to cell fusion as a link between viruses and cancer

    Nat Rev Cancer

    (2007)
  • H.O. Lee et al.

    Endoreplication: polyploidy with purpose

    Genes Dev

    (2009)
  • K. Ravid et al.

    R. Roads to polyploidy: the megakaryocyte example

    J Cell Physiol

    (2002)
  • D. Dikovskaya et al.

    Loss of APC induces polyploidy as a result of a combination of defects in mitosis and apoptosis

    J Cell Biol

    (2007)
  • U.S. Eggert et al.

    Animal cytokinesis: from parts list to mechanisms

    Annu Rev Biochem

    (2006)
  • J.M. Mullins et al.

    Terminal phase of cytokinesis in D-98Ā s cells

    J Cell Biol

    (1977)
  • Q. Shi et al.

    Chromosome nondisjunction yields tetraploid rather than aneuploid cells in human cell lines

    Nature

    (2005)
  • G. Margall-Ducos et al.

    Liver tetraploidization is controlled by a new process of incomplete cytokinesis

    J Cell Sci

    (2007)
  • L. Germain et al.

    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)
  • N. Shiojiri et al.

    Cell lineages and oval cell progenitors in rat liver development

    Cancer Res

    (1991)
  • Cited by (57)

    • Stem cell therapy in liver regeneration: Focus on mesenchymal stem cells and induced pluripotent stem cells

      2022, Pharmacology and Therapeutics
      Citation Excerpt :

      While polyploid hepatocytes reduce their proliferation capacity with aging and pathological processes, they act as growth inhibitors to limit the proliferation of most hepatocytes, and senescent polyploid hepatocytes can be regenerated through ploidy reversal. When hepatocellular carcinoma occurs, it is mainly driven by diploid hepatocytes, so induction of polyploidy may be a potential strategy for cancer treatment(F. Chen et al., 2020; Gentric, Celton-Morizur, & Desdouets, 2012; Gupta, 2000; M. J. Wang et al., 2017; Wilkinson et al., 2019). Therefore, understanding the mechanism of liver regeneration is crucial for the treatment of various liver diseases.

    • The Significance of Polyploid Hepatocytes During Aging Process

      2021, Cellular and Molecular Gastroenterology and Hepatology
    • In Vivo Lineage Tracing of Polyploid Hepatocytes Reveals Extensive Proliferation during Liver Regeneration

      2020, Cell Stem Cell
      Citation Excerpt :

      This multipolar reductive mitosis might enhance effective organ regeneration by generating more than two cells in one cell division. On the other hand, some studies have shown that polyploid hepatocytes exhibit senescence-associated changes following one or two rounds of cell division (Gentric et al., 2012; Sigal et al., 1999). Additionally, it has been suggested that diploid hepatocytes adjacent to the central vein of the liver lobule act as stem cells during homeostasis and injury response (Wang et al., 2015).

    • Aryl Hydrocarbon Receptor Promotes Liver Polyploidization and Inhibits PI3K, ERK, and Wnt/Ī²-Catenin Signaling

      2018, Food Science and Human Wellness
      Citation Excerpt :

      Nevertheless, certain organisms can undergo successive rounds of genome duplication in the absence of cytokinesis to acquire a polyploid status that can involve the whole organism or just specific tissues and organs (Edgar et al., 2014; Fox and Duronio, 2013; Schoenfelder and Fox, 2015). Among mammals, including humans, polyploidy is particularly relevant in the liver hepatocytes, megakaryocytes, and placental giant trophoblast cells, although it also takes place in the heart and muscle (Gentric et al., 2012; Hannibal et al., 2014). In the liver, the percentage of polyploid hepatocytes ranges from 80% to 90% in rats, to 30% in humans, and to close to 50% in mice (Celton-Morizur et al., 2010; Duncan et al., 2010).

    View all citing articles on Scopus
    View full text