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.

TGFbeta Induces Binucleation/Polyploidization in Hepatocytes through a Src-Dependent Cytokinesis Failure

“…After a preliminary experiment on WT/3A hepatocytes, in which we verified the efficacy of the inhibitor to impair the TGFbeta signaling (analyzing the level of phosphorylated Smad3) and the binucleation rate (S2A and S2B Fig respectively, lanes 1–4), LY2109761 was administered to mice as described in Fig 2A. The treatment timing and the dosage were in accord to previous works reporting the weaning period as the frame time in which binucleation occurs [2, 3] and 100mg/Kg as the daily dose able to inhibit the TGFbeta signaling in vivo [28–30]. …”

“…Liver polyploidization is a process specifically occurring during the weaning period: at birth, mammals show a fully mononucleated liver tissue, whereas during the first post-natal months binucleated and mononucleated parenchymal cells with a higher content of DNA are produced [2, 3]. The binucleation of hepatocytes represents the first step of the polyploidization process and it has been demonstrated to be dependent on a cytokinesis failure [4].…”

When bigger is better: the role of polyploidy in organogenesis

“…There is a mouse cell line of TGC precursor cells that can be induced to endocycle by the removal of Fibroblast Growth Factor 4 [74]. TGF-β signaling is involved in promoting the endocycle in the nematode hypodermis [57, 58], and insulin-Akt signaling promotes hepatocyte polyploidization [75]. Further research is necessary to determine whether pathways such as Notch, insulin and TGF-β are used universally to control polyploidization and how much diversity exists in distinct developmental contexts.…”

The Cardiomyocyte Cell Cycle in Hypertrophy, Tissue Homeostasis, and Regeneration

“…Liver hepatocytes also binucleate during postnatal development by cytokinesis failure. However, unlike cardiomyocytes, hepatocytes appear to maintain some level of proliferative-and regenerative-competence (Gentric et al 2012). This has led many to speculate that the key to adult cardiomyocyte proliferative-competence lies within hepatocyte biology.…”