Implications of Polyploidy and Ploidy Alterations in Hepatocytes in Liver Injuries and Cancers

Abstract

Polyploidy, a condition in which more than two sets of chromosomes are present in a cell, is a characteristic feature of hepatocytes. A significant number of hepatocytes physiologically undergo polyploidization at a young age. Polyploidization of hepatocytes is enhanced with age and in a diseased liver. It is worth noting that polyploid hepatocytes can proliferate, in marked contrast to other types of polyploid cells, such as megakaryocytes and cardiac myocytes. Polyploid hepatocytes divide to maintain normal liver homeostasis and play a role in the regeneration of the damaged liver. Furthermore, polyploid hepatocytes have been shown to dynamically reduce ploidy during liver regeneration. Although it is still unclear why hepatocytes undergo polyploidization, accumulating evidence has revealed that alterations in the ploidy in hepatocytes are involved in the pathophysiology of liver cirrhosis and carcinogenesis. This review discusses the significance of hepatocyte ploidy in physiological liver function, liver injury, and liver cancer.

The Ploidy State as a Determinant of Hepatocyte Proliferation

“…Matsumoto and colleagues again used lineage tracing models to investigate the role of polyploidy and ploidy reversal during oncogenesis. 74 75 In response to induced tumorigenesis (nonalcoholic steatosis, FAH deficiency, and thioacetamide injury), multiple tumor lineages emerged, including bicolored tumors (derived from polyploid hepatocytes) and monocolored tumors (originally from ploidy reversal-derived diploids). Furthermore, a direct comparison of the tumorigenic potential of (1) ploidy reversal-competent hepatocytes and (2) experimentally induced incompetent hepatocytes revealed up to a seven-fold increase in tumor formation by hepatocytes capable of ploidy reversal.…”

“…3A-C). 20,74 Although polyploidy can protect against liver cancer, polyploid hepatocytes are not immune to carcinogenesis (see Ploidy and Oncogenic Proliferation). Matsumoto and colleagues again used lineage tracing models to investigate the role of polyploidy and ploidy reversal during oncogenesis.…”

“…Together, these data indicate that ploidy reversal and subsequent re-polyploidization are common features of hepatocyte proliferation, seen in each injury model examined (Figure 3A-C). 20,74 Although polyploidy can protect against liver cancer, polyploid hepatocytes are not immune to carcinogenesis (see Ploidy and oncogeneic proliferation). Matsumoto and colleagues again used lineage tracing models to investigate the role of polyploidy and ploidy reversal during oncogenesis.…”

Liver regeneration by oval cells employing bistability of stemness-senescence, Hippo signaling, EMT-MET, and polyploidy circuit

“…The Hippo pathway, one of the central growth regulators, was shown to accompany the whole healing process from cell activation to the termination of response [6]. This pathway is involved in replicative stress [7], and cellular polyploidy, which is described in normal liver and boosted by regeneration [8, 9]. Senescence is another mechanism involved in liver repair; however, its role is controversial and poorly understood [10, 11].…”

Deep-Learning-Based Hepatic Ploidy Quantification Using H&E Histopathology Images

“…Lin et al found that the hyperpolyploidization of hepatocytes around the centrilobular (CL) region is closely linked with the development of HCC cells after diethylnitrosamine treatment [ 19 ]. Overall, the function of polyploid hepatocytes has not yet been fully understood and needs further exploration [ 22 , 23 , 24 ]. Therefore, the improved characterization of the frequency and number of polyploid cells in both normal and diseased human livers would be important.…”