Hepatocytes polyploidization and cell cycle control in liver physiopathology

Abstract

Most cells in mammalian tissues usually contain a diploid complement of chromosomes. However, numerous studies have demonstrated a major role of "diploid-polyploid conversion" during physiopathological processes in several tissues. In the liver parenchyma, progressive polyploidization of hepatocytes takes place during postnatal growth. Indeed, at the suckling-weaning transition, cytokinesis failure events induce the genesis of binucleated tetraploid liver cells. Insulin signalling, through regulation of the PI3K/Akt signalling pathway, is essential in the establishment of liver tetraploidization by controlling cytoskeletal organisation and consequently mitosis progression. Liver cell polyploidy is generally considered to indicate terminal differentiation and senescence, and both lead to a progressive loss of cell pluripotency associated to a markedly decreased replication capacity. Although adult liver is a quiescent organ, it retains a capacity to proliferate and to modulate its ploidy in response to various stimuli or aggression (partial hepatectomy, metabolic overload (i.e., high copper and iron hepatic levels), oxidative stress, toxic insult, and chronic hepatitis etc.). Here we review the mechanisms and functional consequences of hepatocytes polyploidization during normal and pathological liver growth.

Figure 1

Hepatocytes polyploidization during development and in challenging circumstances: (A) polyploidization during postnatal liver growth. Hepatocytes in newborn are exclusively diploid (mononucleated 2n). At the weaning period, diploid hepatocytes can engage either into normal cell division cycle (black arrow) giving rise to two diploid hepatocytes or follow an adaptive cell cycle with cytokinesis failure (red arrow) giving rise to one binucleated tetraploid hepatocyte. By this process, progressive polyploidization takes place in the liver parenchyma and tetraploid and octoploid cell classes with one or two nuclei are formed. (B) Ploidy modification during physiopathological processes in adult liver. In adult, liver modulates its ploidy in response to different signals. Liver regeneration induced by partial hepatectomy leads to the disappearance of binucleated hepatocytes and the formation of mononucleated tetraploid and octoploid hepatocytes or even 16n contingent. DNA synthesis induced by chemicals or following oxidative damage and metabolic overload (copper/iron) is associated with a pronounced increase in the proportion of polyploid hepatocytes. Furthermore, in response to different unknown signals, hepatocytes can both increase (bipolar mitosis followed by cytokinesis failure) or decrease their ploidy (multipolar mitosis). In that case, near-diploid/near-polyploid contingents will be generated, leading to the genesis of genetically distinct daughter cells; black arrow: complete cytokinesis, red arrow: cytokinesis failure.