A new study finds that diploid hepatocytes proliferate faster than their polyploid counterparts, suggesting that polyploid status functions as a growth suppressor in the liver. The data inform research on liver oncogenesis and regeneration.

Polyploid hepatocytes represent >50% of the hepatocyte population in human livers, but the roles of diploid and polyploid cells in homeostasis and disease are not fully understood. Research has been hampered by a dearth in suitable animal models and the ability of hepatocytes to change their ploidy status during proliferation.

In a new paper, Wilkinson et al. used mice with liver-specific E2F7 and E2F8 double-knockout (LKO), which are functionally comparable to control animals. Measuring hepatocyte ploidy status, livers from LKO mice contained 20-fold more diploid and 3-fold fewer polyploid hepatocytes than those of control mice. In contrast to other settings, polyploidy in hepatocytes has been suggested to be protective against tumorigenesis. Indeed, using a diethylnitrosamine–phenobarbital liver tumour model, the researchers found profuse tumour formation in LKO mice but not in control mice livers. In a transplantation experiment, the team noticed that LKO hepatocytes repopulated livers faster than control hepatocytes. Further testing showed that control hepatocytes were outcompeted by faster-proliferating LKO hepatocytes.

To avoid confounding effects of the LKO, the team analysed proliferation of wild-type hepatocytes and found that diploid cells entered and progressed through the cell cycle faster than polyploid cells in vitro and in vivo. Finally, the team tested whether ploidy status altered sensitivity to growth factors, finding similar responses in both diploid and polyploid hepatocytes.