Polyploidy associated with oxidative injury attenuates proliferative potential of cells

Polyploid cells are encountered ubiquitously but the biological significance of polyploidy is unclear. In view of their extensive capacity for regeneration, hepatocytes offer excellent systems for analyzing growth control mechanisms. We isolated hepatocytes from adult rats with and without two-third partial hepatectomy, which induces hepatic polyploidy. Polyploid hepatocytes showed evidence for oxidative injury with antioxidant depletion, lipid peroxidation and 8-hydroxy-adducts of guanine in nuclear DNA. Liver repopulation assays in intact animals showed markedly decreased replication capacity in polyploid hepatocytes. Recapitulation of polyploidy in cultured hepatocytes established that mitogenic stimulation in the presence of oxidative DNA injury was capable of inducing polyploidy. The findings provide novel frameworks in the context of polyploidy for understanding tissue development, regeneration and oncogenesis.