RPE Differentiation is a Selective Barrier Against Aneuploid hESC

Abstract In this study, we show that undirected differentiation of human embryonic stem cells (hESC) to retinal pigment epithelium (RPE) acts as a selective barrier against aneuploid cells. Large-scale omics analysis reveals that 3–6% of cells of genetically normal hESC cultures are aneuploid, none of which progresses through RPE differentiation except for cells with a gain of 1q. We show that while all homogeneously aneuploid hESC lines carrying an array of different abnormalities have impaired RPE differentiation, co-culture with genetically normal cells specifically rescues the differentiation of cells with a gain of 1q. In turn, these aneuploid cells have an in vitro growth advantage, and progressively take over the differentiating culture. Time-course analysis shows that, only when co-cultured, cells with a gain of 1q follow the same differentiation path as genetically normal cells, which support the mutant cells by secreting extracellular matrix and ligands promoting differentiation.