Polyploid Hepatocytes Facilitate Adaptation and Regeneration to Chronic Liver Injury.

The liver contains diploid and polyploid hepatocytes (tetraploid, octaploid, etc.), with polyploids comprising ≥90% of the hepatocyte population in adult mice. Polyploid hepatocytes form multipolar spindles in mitosis, which lead to chromosome gains/losses and random aneuploidy. The effect of aneuploidy on liver function is unclear, and the degree of liver aneuploidy is debated, with reports showing aneuploidy affects 5% to 60% of hepatocytes. To study the relationship between liver polyploidy, aneuploidy, and adaptation, mice lacking E2f7 and E2f8 in the liver (LKO), which have a polyploidization defect, were used. Polyploids were reduced 4-fold in LKO livers, and LKO hepatocytes remained predominantly diploid following extensive proliferation. Moreover, nearly all LKO hepatocytes were euploid compared to control hepatocytes, suggesting polyploid hepatocytes are required for production of aneuploid progeny. To determine if reduced polyploidy impairs adaptation, LKO mice were bred onto a tyrosinemia background, a disease model where the liver can develop disease-resistant, regenerative nodules. Although tyrosinemic LKO mice were more susceptible to morbidities and death associated with tyrosinemia-induced liver failure, they developed regenerating nodules similar to controls. Analyses revealed that the nodules in the tyrosinemic livers were generated via aneuploidy and inactivating mutations. In summary, we identified new roles for polyploid hepatocytes and demonstrated that they are required for the formation of aneuploid progeny and can facilitate adaptation to chronic liver disease.