Hepatocyte polyploidization and its association with pathophysiological processes

Abstract

A characteristic cellular feature of the mammalian liver is the progressive polyploidization of the hepatocytes, where individual cells acquire more than two sets of chromosomes. Polyploidization results from cytokinesis failure that takes place progressively during the course of postnatal development. The proportion of polyploidy also increases with the aging process or with cellular stress such as surgical resection, toxic stimulation, metabolic overload, or oxidative damage, to involve as much as 90% of the hepatocytes in mice and 40% in humans. Hepatocyte polyploidization is generally considered an indicator of terminal differentiation and cellular senescence, and related to the dysfunction of insulin and p53/p21 signaling pathways. Interestingly, the high prevalence of hepatocyte polyploidization in the aged mouse liver can be reversed when the senescent hepatocytes are serially transplanted into young mouse livers. Here we review the current knowledge on the mechanism of hepatocytes polyploidization during postnatal growth, aging, and liver diseases. The biologic significance of polyploidization in senescent reversal, within the context of new ways to think of liver aging and liver diseases is considered.

Figure 1

The distribution of ploidy classes in different mammals. The graphs show the percentage of diploid, tetraploid, and octoploid hepatocytes in newborn, adult, and aged human, mice and rat. Adult mice and rats were 8–12 weeks old; adult human were 20–40 years old. Aged mice were over 18 months, and aged human were over 60 years old. The data were compiled from published studies (Duncan AW, et al.; Wang MJ, et al.; Chipchase MD, et al.; Pandit SK, et al.; Margall-Ducos G, et al.; Gandillet A, et al.; Kudryavtsev BN, et al.; Duncan AW, et al.)

Figure 2

Polyploidization during postnatal liver growth. From the postnatal growth, a diploid hepatocyte can give rise to two diploid hepatocytes with successful cytokinesis or follows with cytokinesis failure and generates a tetraploid hepatocyte with two diploid nuclei. The binucleated tetraploid hepatocyte then follows a new round cell cycle, generating two mononucleated tetraploids or one binucleated octoploidy. In the adult liver parenchyma, it consists of diploid, tetraploid and octoploid hepatocytes. Insulin signaling, E2F transcription factors including E2F8 and E2F1, and miR-122 have been reported to regulate cytokinesis failure and be crucial for liver polyploidization during postnatal development

Figure 3

Senescent polyploid hepatocytes are rejuvenated accompanied by ploidy converyor. In the aged liver, senescent polyploid hepatocytes reenter cell cycles after transplantation. These proliferating tetraploid or octoploid hepatocytes can generate mononucleated diploid and tetraploid hepatocytes, as well as binucleated tetraploidy with triploar or double mitosis. Accompanied with senescent hepatocytes reversal, the percentage of octoploid hepatocytes decreases while the percentage of diploid hepatocytes increases. The p16^ink4α and p53-p21 pathway regulating hepatocyte senescence may be a mechanism of polyploidization during aging

Figure 4

Pathological polyploidization in the liver. In the pathological liver, hepatocytes progress through G1 and enter S-phase, but fail with cell mitosis, leading to formation of mononucleated polyploid hepatocytes. The G2/M arrest is controlled by p53/p21 signaling pathway