1q gain bypasses the selective barrier against aneuploidy in RPE differentiation via wild-type co-culture rescue.

Human pluripotent stem cells (hPSC) are increasingly used in clinical trials, with retinal pigment epithelium (RPE) being among the most transplanted cell types. However, hPSC frequently acquire chromosomal abnormalities, whose impact on differentiation and transplant safety is incompletely understood. In this work, we investigate how aneuploidy influences the progression of hPSC through undirected RPE differentiation. Large-scale omics analysis of genetically normal hPSC cultures reveals pervasive low-grade mosaicism, with 3-6% of cells carrying different aneuploidies. During undirected differentiation, all aneuploid cells are lost except those with a gain of chromosome arm 1q. These cells differentiate efficiently only when co-cultured with wild-type cells, which promote neural differentiation through paracrine signals that 1q-gain cells are uniquely receptive to. This interaction enables 1q-gain cells not only to persist but to eventually dominate the culture, owing to their competitive advantage.