Hepatocyte polyploidization and its association with pathophysiological processes

Abstract

A characteristic cellular feature of the mammalian liver is the progressive polyploidization of the hepatocytes, where individual cells acquire more than two sets of chromosomes. Polyploidization results from cytokinesis failure that takes place progressively during the course of postnatal development. The proportion of polyploidy also increases with the aging process or with cellular stress such as surgical resection, toxic stimulation, metabolic overload, or oxidative damage, to involve as much as 90% of the hepatocytes in mice and 40% in humans. Hepatocyte polyploidization is generally considered an indicator of terminal differentiation and cellular senescence, and related to the dysfunction of insulin and p53/p21 signaling pathways. Interestingly, the high prevalence of hepatocyte polyploidization in the aged mouse liver can be reversed when the senescent hepatocytes are serially transplanted into young mouse livers. Here we review the current knowledge on the mechanism of hepatocytes polyploidization during postnatal growth, aging, and liver diseases. The biologic significance of polyploidization in senescent reversal, within the context of new ways to think of liver aging and liver diseases is considered.

Tetraploidy in cancer and its possible link to aging

“…In support of our observations in the tetraploidy‐prone mice, the population of tetraploid cells is elevated at several organs during normal aging . For example, some hepatocytes increase their ploidy, becoming tetraploid and octoploid, during the aging process . In the liver, some polyploid cells are likely to develop into aneuploid ones .…”

“…68,69 For example, some hepatocytes increase their ploidy, becoming tetraploid and octoploid, during the aging process. 70,71 In the liver, some polyploid cells are likely to develop into aneuploid ones. 12 The phenotypes of our mice resemble those of aneuploidy-prone mice such as BubR1-hypomorphic 61 or Bub3/Rae1haploinsufficient 72 mice.…”

A Single‐Cell Perspective of the Mammalian Liver in Health and Disease

“…As such, hepatic steatosis is most conspicuously observed in pericentral hepatocytes in patients with NAFLD, likely reflecting their role in lipogenesis and triglyceride synthesis. Hepatocytes are known to harbor polyploid genomes contained within one or two nuclei in the cell . This heterogeneity of hepatocyte polyploidization and its associated transcriptomic signature represent yet another dimension of liver cell heterogeneity that is primed for exploration using single‐cell technologies.…”

“…Hepatocytes are known to harbor polyploid genomes contained within one or two nuclei in the cell. (8) This heterogeneity of hepatocyte polyploidization and its associated transcriptomic signature represent yet another dimension of liver cell heterogeneity that is primed for exploration using single-cell technologies.…”

Fast and efficient generation of knock-in human organoids using homology-independent CRISPR/Cas9 precision genome editing

“…The liver is characterized by the presence of polyploid hepatocytes, cells with more than two sets of chromosomes. These cells generally tend to increase in number with age and upon injury 42 . Past studies have suggested that polyploid hepatocytes predominantly originate from incomplete cytokinesis 43,44 .…”