Abstract
Simple SummaryPolyploidy, a balanced amplification of the genome is a defining feature of the liver. Up to 90% of adult hepatocytes in rodents and around 40% of those in humans are polyploid. The polyploidy of these cells depends on both the DNA content of each nucleus (nuclear ploidy) and the number of nuclei per cell (cellular ploidy). Remarkably, the liver is one of the few mammalian organs that display changes in ploidy content during normal homeostasis, regeneration and pathological conditions. Although polyploid hepatocytes were documented over a century ago, the significance of this original phenomenon in the pathophysiology of the liver remains unclear. In this review, we focused on the mechanisms regulating hepatocyte polyploidization both during liver development and under pathological conditions. We also detailed the effects of polyploidy on liver function and explored the fate and the role of the polyploid state during chronic liver diseases.Polyploidy, also known as whole-genome amplification, is a condition in which the organism has more than two basic sets of chromosomes. Polyploidy frequently arises during tissue development and repair, and in age-associated diseases, such as cancer. Its consequences are diverse and clearly different between systems. The liver is a particularly fascinating organ in that it can adapt its ploidy to the physiological and pathological context. Polyploid hepatocytes are characterized in terms of the number of nuclei per cell (cellular ploidy; mononucleate/binucleate hepatocytes) and the number of chromosome sets in each nucleus (nuclear ploidy; diploid, tetraploid, octoploid). The advantages and disadvantages of polyploidy in mammals are not fully understood. About 30% of the hepatocytes in the human liver are polyploid. In this review, we explore the mechanisms underlying the development of polyploid cells, our current understanding of the regulation of polyploidization during development and pathophysiology and its consequences for liver function. We will also provide data shedding light on the ways in which polyploid hepatocytes cope with centrosome amplification. Finally, we discuss recent discoveries highlighting the possible roles of liver polyploidy in protecting against tumor formation, or, conversely, contributing to liver tumorigenesis.
Highlights
Introduction conditions of the Creative CommonsEukaryotic organisms usually contain two complete haploid sets of homologous chromosomes
The entry into and progression through each step are tightly regulated by a number of different proteins, including cyclin-dependent kinases (CDKs) and cyclins, the catalytic activity of which is stimulated by tight binding to CDKs
Competitive tumor formation assays have revealed that ploidy reduction during the early steps of carcinogenesis plays a greater role in models of tumorigenesis induced by tumor suppressor loss than in oncogeneinduced cancer models [128]. These data highlight the possibility that proliferating polyploid hepatocytes engaged in a ploidy reduction mechanism may provide a reservoir of low-ploidy cells susceptible to both loss of heterozygosity (LOH) and chromosome instability (CIN), two processes widely implicated in malignant transformation [129,130]
Summary
Eukaryotic organisms usually contain two complete haploid sets of homologous chromosomes (diploidy, 2 n). Polyploidy, or whole-genome duplication, is the condition in which an organism or cell contains additional sets of chromosomes (e.g., 4 n, 8 n). Many species that are currently diploid, including humans, are derived from polyploid ancestors [5,6]. These species, who experienced ancient genome duplications followed by genome reduction, are known as paleopolyploids. Whole-organism polyploidy may be rare, but polyploid cells are present at relatively high frequency in many mammalian tissues [10,11,12,13]. Polyploidy has been shown to be associated with tumor progression, in particular due to its association with the development of chromosome instability (CIN) [21,22,23]
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