The whole-genome duplication is a barrier for iPSCs reprogramming from mouse fibroblasts

Whole-genome duplication (WGD) -induced tetraploidization represents a pivotal genetic event widely investigated in the contexts of tumorigenesis, developmental processes, and evolutionary biology, whereas its functional consequences for somatic cell reprogramming have yet to be elucidated. Here we show that mouse embryonic fibroblasts (MEFs) undergo spontaneous WGD in vitro. However, the resulting tetraploid cells are refractory to iPSCs reprogramming. Mechanistically, the tetraploidization of MEFs is p38-dependent. Pretreatment with p38 inhibitor SB203580 suppresses cytokinesis failure-induced binucleation and significantly enhances reprogramming efficiency. We further identify the elevated p53 accumulation in binucleated cells as the primary barrier to reprogramming, as its depletion rescues iPSCs formation in tetraploid cells. These findings reveal the whole-genome duplication exerts distinct regulatory control over cell fate transition.