Abstract
The appearance of genetic changes in human pluripotent stem cells (hPSCs) presents a concern for their use in research and regenerative medicine. Variant hPSCs harbouring recurrent culture-acquired aneuploidies display growth advantages over wild-type diploid cells, but the mechanisms yielding 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 resulting in 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 YAP in the cytoplasm that induces apoptosis in wild-type cells. Importantly, YAP overexpression in wild-type cells is sufficient to alleviate their loser phenotype. Our results demonstrate that hPSC fate is coupled to mechanical cues imposed by neighbouring cells and reveal that hijacking this mechanism allows variants to achieve clonal dominance in cultures.
Highlights
The ability of cells to influence their neighboring cells’ fate choices has become apparent from studies in various in vitro and in vivo models
Variant human pluripotent stem cells (hPSCs) selectively eliminate diploid wild-type counterparts from co-cultures To uncover the reasons behind the rapid overtake of cultures by genetically variant hPSCs (Olariu et al, 2010), we sought to examine how wild-type and genetically variant hPSCs interact and whether they affect each other’s growth
We initially used two diploid H7 sublines, and their aneuploid variant harboring a gain of chromosomes 1, 12, 17q, and 20q copy number variant (CNV), and stably expressing green fluorescent protein (GFP)
Summary
The ability of cells to influence their neighboring cells’ fate choices has become apparent from studies in various in vitro and in vivo models. An example of this is cell competition, a type of cell-cell interaction wherein viable but less-fit ‘‘loser’’ cells are outcompeted for nutrients or space and eventually eliminated by the fitter ‘‘winner’’ cells (Bowling et al, 2019). In the field of regenerative medicine, the fundamental question of how mutant cells may influence behavior of their wild-type counterparts has been brought into focus by observation that human pluripotent stem cells (hPSCs) acquire genetic changes upon prolonged passaging (Draper et al, 2004; International Stem Cell et al, 2011). The implications of the variant presence could be significant for therapeutic and research uses of hPSCs, as altered behavior of variant cells could impact on the efficiency of differentiation protocols, functionality of differentiated cells, or the safety of cell replacement therapies (Andrews et al, 2017; Halliwell et al, 2020)
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