In understanding mechanisms of liver repopulation with transplanted hepatocytes, we studied the consequences of hepatic polyploidization in the two-thirds partial
hepatectomy model of liver regeneration. Liver repopulation studies using genetically marked rodent hepatocytes showed that the number of previously transplanted hepatocytes did not increase in the liver with subsequential partial
hepatectomy. In contrast, recipients undergoing partial
hepatectomy before cells were transplanted showed proliferation in transplanted hepatocytes, with kinetics of
DNA synthesis differing in transplanted and host hepatocytes. Also, partial
hepatectomy caused multiple changes in the rat liver, including accumulation of
polyploid hepatocytes along with prolonged depletion of diploid hepatocytes, as well as increased senescence-associated
beta-galactosidase and p21 expression. Remnant hepatocytes in the partially hepatectomized liver showed increased autofluorescence and cytoplasmic complexity on flow cytometry, which are associated with
lipofuscin accumulation during cell aging, and underwent apoptosis more frequently. Moreover, hepatocytes from the partially hepatectomized liver showed attenuated proliferative capacity in cell culture. These findings were compatible with decreased proliferative potential of hepatocytes experiencing partial
hepatectomy compared with hepatocytes from the unperturbed liver. Attenuation of proliferative capacity and other changes in hepatocytes experiencing partial
hepatectomy offer novel perspectives concerning liver regeneration in the context of cell ploidy.