The immediate cellular response to whole-genome doubling is conserved across polyploid contexts

Polyploid cells, which contain more than two copies of the genome, are widely present across plants and animals, where they are often found in tissues with high biosynthetic and metabolic demands, such as the mammalian liver and placenta. While somatic polyploidy is frequently associated with increased cell growth and biosynthetic capacity, unscheduled polyploidization in cell types that are not normally programmed to become polyploid is often linked to reduced cellular fitness and genome instability. To understand whether these divergent outcomes stem from distinct immediate cellular responses to increased ploidy, we systematically compared the early consequences of polyploidization across naturally occurring and experimentally induced systems. Specifically, we examined physiological polyploid cells in the Caenorhabditis elegans intestine and human hepatocyte organoids, alongside unscheduled polyploid human retinal pigment epithelial (RPE1) cells generated through cytokinesis failure. Using quantitative imaging, flow cytometry, and FUCCI based cell-cycle reporters we measured cell size and protein translation dynamics during G1 in diploid and polyploid cells. Across all systems, we observed a strikingly conserved relationship between ploidy, cell size, and biosynthetic capacity: both cell size and protein translation showed similar scaling patterns after polyploidization, regardless of whether polyploidization occurred as part of normal development or by inducing cytokinesis failure. These findings indicate that the immediate cellular response to increased ploidy is broadly similar across contexts. However, in contrast to unscheduled polyploid RPE1 cells, polyploid human hepatocytes extend their G1 phase, leading to a higher accumulation of proteins before cell-cycle progression. Together, our findings suggest that polyploidization elicits similar growth responses across contexts, and that cell-type specific cell-cycle adaptations may determine whether polyploidy becomes advantageous or deleterious.