Most cells in the liver are polyploid, but the functional role of polyploidy is unknown. Polyploidization occurs through cytokinesis failure and endoreduplication around the time of weaning. To interrogate polyploidy while avoiding irreversible manipulations of essential cell-cycle genes, we developed orthogonal mouse models to transiently and potently alter liver ploidy. Premature weaning, as well as knockdown of E2f8 or Anln, allowed us to toggle between diploid and polyploid states. While there was no detectable impact of ploidy alterations on liver function, metabolism, or regeneration, mice with more polyploid hepatocytes suppressed tumorigenesis and mice with more diploid hepatocytes accelerated tumorigenesis in mutagen- and high-fat-induced models. Mechanistically, the diploid state was more susceptible to Cas9-mediated tumor-suppressor loss but was similarly susceptible to MYC oncogene activation, indicating that polyploidy differentially protected the liver from distinct genomic aberrations. This suggests that polyploidy evolved in part to prevent malignant outcomes of liver injury.

肝脏中的大多数细胞都是多倍体，但多倍体的功能作用尚不清楚。多倍体化通过断奶时的胞质分裂失败和核内复制而发生。为了询问多倍体性，同时避免不可逆的必需细胞周期基因操纵，我们开发了正交小鼠模型来瞬时和有效地改变肝倍性。提前断奶，以及敲除E2f8或Anln，使我们能够在二倍体和多倍体状态之间切换。尽管没有倍性改变对肝功能，代谢或再生的可检测影响，但在诱变和高脂诱导的模型中，具有更多倍性肝细胞的小鼠抑制了肿瘤的发生，而具有更多倍性肝细胞的小鼠则加速了肿瘤的发生。从机理上讲，二倍体状态更易受Cas9介导的肿瘤抑制物丢失的影响，但对MYC癌基因的激活也同样敏感，这表明多倍体状态可差异性地保护肝脏免受明显的基因组异常影响。这表明多倍体进化部分地是为了防止肝损伤的恶性后果。