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Abstract

Hepatocytes have the ability to go through specialized cell cycles, which, during normal developmental liver growth, result in the formation of binuclear and polyploid cells. In the adult rat liver, the majority of the hepatocytes (about 70%) are tetraploid, 15-20% are octoploid, and only 10-15% are diploid (about 50% in humans). One-third of the hepatocytes in either rats or humans are binuclear (with two diploid or two tetraploid nuclei). Among cultured rat hepatocytes stimulated with growth factors (EGF and insulin), one-half of the mitoses are of the binucleating type (suggesting a "quantal" mechanism), causing one-third of the postmitotic cells to become binuclear. In contrast, regenerative liver growth, induced by partial hepatectomy, is predominantly nonbinucleating. During rat liver carcinogenesis, the early populations of phenotypically altered cells (foci) are predominantly diploid, as are the later neoplastic nodules and carcinomas, which can be shown to have a regeneration-like, largely nonbinucleating growth pattern. A negative correlation between growth capacity and ploidy can be demonstrated in cultured hepatocytes, regenerating livers, neoplastic nodules, and hepatocellular carcinomas, suggesting that suppression of binucleation and polyploidization may carry a growth advantage, in addition to helping to maintain a large population of diploid, potential stem cells. Since a diploid genome is less protected against mutagenic change than a polyploid genome, diploid tumor cells may, furthermore, be more prone than polyploid cells to undergo mutation-based progression toward increasing malignancy. The ability of liver tumor promoters like 2-acetylaminofluorene, cyproterone acetate, alpha-hexachlorocyclohexane and methylclofenapate to induce nonbinucleating hepatocyte growth may, therefore, cooperate with the selective growth stimulation of cancer cells and cancer cell precursors to promote liver carcinogenesis. Autophagy, a mechanism for the bulk degradation of cytoplasm, contributes to intracellular protein turnover and serves to restrict cellular growth. Rat liver carcinogenesis is accompanied by a progressive reduction of autophagic capacity, preneoplastic livers having 50% and hepatocellular carcinoma cells only 20% as much autophagy as normal hepatocytes. The ascites hepatoma cell line AH-130 has virtually no autophagy during logarithmic growth, but some autophagy is turned on when the cells become growth-arrested at high cell density. Ascitic fluid from AH-130 cells is able to completely inhibit autophagy in normal hepatocytes, suggesting that the cancer cells may improve their growth ability through an autocrine, autophagy-suppressive mechanism. Hepatocytes from preneoplastic livers similarly maintain a low autophagic activity under restrictive culture conditions, thereby surviving much better than normal hepatocytes, which switch on their autophagy. In the presence of an autophagy inhibitor (3-methyladenine), normal and preneoplastic hepatocytes survive equally well, testifying to the importanc...

Hepatocyte polyploidization and its association with pathophysiological processes

“…Thus, rapidly dividing diploid tumor cells are more easily mutated than the polyploid cells, resulting in increasing malignancy. 47, 48 HCC development is accompanied by decreased expression of miR-122. MiR-122, frequently the most specific miRNA in the liver, is considered necessary and sufficient for liver polyploidization, in addition to being an important tumor suppressor in hepatocellular carcinoma.…”

Hepatocytes Polyploidization and Cell Cycle Control in Liver Physiopathology

“…After weaning (day 21), the proportion of diploid hepatocytes started to fall significantly, with the successive appearance of binucleated tetraploid (2 × 2n) and mononucleated tetraploid (4n) hepatocytes [32, 33] (see Figure 1). The hepatocyte ploidy level effectively reaches a plateau at maturity, octoploid (binucleated 2 × 4n and mononucleated 8n) hepatocytes appearing in significant numbers during the second and third months after birth [42]. Interestingly, a second wave of high ploidization has been also observed at senescence in different species [43].…”

Liver cell polyploidization: A pivotal role for binuclear hepatocytes

“…If we consider the polyploid fraction, 20 -30% of hepatocytes are binuclear (either 2 ϫ 2n or 2 ϫ 4n) (3,4). The degree of polyploidization varies among mammals (5) and particularly in humans, where the number of polyploid cells averages 20 -30% in the adult liver (6,7). Interestingly, in different liver pathologies, hepatocarcinoma for example, hepatocellular growth shifts to a nonpolyploidizing growth pattern, and expansion of the diploid hepatocyte population has been found to take place (4,7).…”

“…One possible explanation is that binuclear 2 ϫ 2n hepatocytes may play a pivotal role in the genesis of mononuclear 4n hepatocytes. Hepatocyte binucleation results from either a defect in the cytokinesis of mononuclear 2n cells (3,7) or the fusion of two mononuclear 2n cells (10). Thereafter, binuclear 2 ϫ 2n hepatocytes may divide, leading to the genesis of two daughter mononuclear 4n hepatocytes.…”