Hepatocyte Polyploidy: Driver or Gatekeeper of Chronic Liver Diseases

SIMPLE SUMMARY: Polyploidy, 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. ABSTRACT: 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.