Reversal of hepatocyte senescence after continuousin vivocell proliferation

Abstract

A better understanding of hepatocyte senescence could be used to treat age-dependent disease processes of the liver. Whether continuously proliferating hepatocytes could avoid or reverse senescence has not yet been fully elucidated. We confirmed that the livers of aged mice accumulated senescent and polyploid hepatocytes, which is associated with accumulation of DNA damage and activation of p53-p21 and p16 ink4a -pRB pathways. Induction of multiple rounds continuous cell division is hard to apply in any animal model. Taking advantage of serial hepatocyte transplantation assays in the fumarylacetoacetate hydrolase-deficient (Fah 2/2 ) mouse, we studied the senescence of hepatocytes that had undergone continuous cell proliferation over a long time period, up to 12 rounds of serial transplantations. We demonstrated that the continuously proliferating hepatocytes avoided senescence and always maintained a youthful state. The reactivation of telomerase in hepatocytes after serial transplantation correlated with reversal of senescence. Moreover, senescent hepatocytes harvested from aged mice became rejuvenated upon serial transplantation, with full restoration of proliferative capacity. The same findings were also true for human hepatocytes. After serial transplantation, the high initial proportion of octoploid hepatocytes decreased to match the low level of youthful liver. Conclusion: These findings suggest that the hepatocyte "ploidy conveyer" is regulated differently during aging and regeneration. The findings of reversal of hepatocyte senescence could enable future studies on liver aging and cell therapy. (HEPATOLOGY 2014;60:349-361)

Elimination of Tumor Suppressor Proteins during Liver Carcinogenesis

“…57 Another study of liver proliferation in aged mice revealed that p16 is elevated in livers of old mice and contributes to the weak proliferative response of livers to PH. 58 Studies of 130 old human patients who underwent hepatectomy showed that these patients had much higher levels of p16 and that these levels negatively correlated with liver regeneration. 59 Examination of mutation/expression of p16 and Rb proteins in human liver cancer and in animal models of carcinogenesis strongly indicated that the loss of functions of these proteins is involved in development of severe liver cancer.…”

Dynamic zonation of liver polyploidy

“…As a result, hepatocytes that reside at the upstream periportal zone differ from hepatocytes in the downstream perivenous zone in the expression of key metabolic genes, a phenomenon termed 'metabolic zonation' (Gebhardt 1992;Jungermann and Keitzmann 1996;Braeuning et al 2006;Colnot and Perret 2011). A second ubiquitous source of liver heterogeneity is its polyploidy (Celton-Morizur et al 2009;Celton-Morizur and Desdouets 2010;Duncan et al 2010;Pandit et al 2012;Gentric and Desdouets 2014;Wang et al 2014;Duncan 2013). Unlike most tissues, the liver is a mixture of hepatocytes that contain either one or two nuclei, each with either 2, 4, 8 or more haploid chromosome sets.…”

Regulation of cytokinesis and its clinical significance

“…However, the discovery of ploidy conveyor 63 has opened a new vision of the field. Polypoidy reversibility explains how polyploid hepatocytes could produce diploid progeny in order to match the low level of youthful liver and restore the proliferative capacity 122 . For instance, after xenotransplantation, old hepatocytes could repopulate the liver to the same degree that 2-month-old hepatocytes did.…”

“…Rise in the binucleation rate is more frequent than other polyploid forms 114 Ploidy conveyor would also allow hepatocytes respond to xenobiotic or nutritional injury 63 Adaptative response to loss of function by acquiring more gene copies 122 Oxidative stress may play a main role in binucleation induction 115 Final result of compensatory liver growth after injury 117 kinase 3 beta (GSK3b) have been described as cytoskeleton regulators [68][69][70] . Similarly, excess glucose feeding to intact mice resulted in polyploidization of pancreatic b cells 71 .…”