Cell competition eliminates aneuploid human pluripotent stem cells

Human pluripotent stem cells (hPSCs) maintain diploid populations for generations despite frequent mitotic errors that cause aneuploidy or chromosome imbalances. Consequently, aneuploid hPSC propagation must be prevented to sustain genome stability, but how this is achieved is unknown. Surprisingly, we find that, unlike somatic cells, uniformly aneuploid hPSC populations with heterogeneous abnormal karyotypes proliferate. Instead, in mosaic populations, cell-non-autonomous competition between neighboring diploid and aneuploid hPSCs eliminates less fit aneuploid cells, regardless of specific chromosome imbalances. Aneuploid hPSCs with lower MYC or higher p53 levels relative to diploid neighbors are outcompeted but conversely gain an advantage when MYC and p53 relative abundance switches. Thus, MYC- and p53-driven cell competition preserves hPSC genome integrity despite their low mitotic fidelity and intrinsic capacity to proliferate with an aneuploid genome. These findings have important implications for using hPSCs in regenerative medicine and for how diploid human embryos form during development despite the prevalence of aneuploidy.