The appearance of genetic changes in human pluripotent stem cells (hPSCs) presents a concern for their use in research and regenerative medicine. Variant hPSCs that harbor recurrent culture-acquired aneuploidies display growth advantages over wild-type diploid cells, but the mechanisms that yield a drift from predominantly wild-type to variant cell populations remain poorly understood. Here, we show that the dominance of variant clones in mosaic cultures is enhanced through competitive interactions that result in the elimination of wild-type cells. This elimination occurs through corralling and mechanical compression by faster-growing variants, causing a redistribution of F-actin and sequestration of yes-associated protein (YAP) in the cytoplasm that induces apoptosis in wild-type cells. YAP overexpression or promotion of YAP nuclear localization in wild-type cells alleviates their “loser” phenotype. Our results demonstrate that hPSC fate is coupled to mechanical cues imposed by neighboring cells and reveal that hijacking this mechanism allows variants to achieve clonal dominance in cultures.

人类多能干细胞 (hPSC) 中基因变化的出现引起了人们对其在研究和再生医学中的应用的担忧。具有反复培养获得性非整倍性的变异 hPSC 比野生型二倍体细胞表现出生长优势，但产生从主要野生型细胞群到变异细胞群的漂移的机制仍知之甚少。在这里，我们表明，嵌合培养物中变异克隆的优势通过竞争性相互作用得到增强，从而导致野生型细胞的消除。这种消除是通过快速生长的变体的聚集和机械压缩来实现的，导致 F-肌动蛋白重新分布，并隔离 yes 相关蛋白 (YAP) 在细胞质中，从而诱导野生型细胞凋亡。YAP 在野生型细胞中过度表达或促进 YAP 核定位可减轻其“失败者”表型。我们的结果表明，hPSC 的命运与邻近细胞施加的机械信号相关，并揭示劫持这一机制使得变异体能够在培养物中实现克隆优势。