Partial hepatectomy-induced polyploidy attenuates hepatocyte replication and activates cell aging events

TLDR

The study aimed to elucidate how hepatic polyploidization affects liver repopulation by transplanted hepatocytes in a two‑thirds partial hepatectomy model. Researchers examined the impact of partial hepatectomy on hepatocyte polyploidization and subsequent liver regeneration using transplanted hepatocytes. Partial hepatectomy before transplantation promoted proliferation of transplanted hepatocytes, whereas transplantation after hepatectomy did not increase cell numbers, and the procedure also induced polyploidy, senescence markers, lipofuscin accumulation, apoptosis, and reduced proliferative capacity, indicating that partial hepatectomy attenuates hepatocyte replication and activates aging events.

Abstract

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 β-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.