Genetically variant human pluripotent stem cells selectively eliminate wild-type counterparts through YAP-mediated cell competition

被引:36
作者
Price, Christopher J. [1 ,2 ]
Stavish, Dylan [1 ,2 ]
Gokhale, Paul J. [1 ]
Stevenson, Ben A. [1 ]
Sargeant, Samantha [1 ,3 ]
Lacey, Joanne [1 ]
Rodriguez, Tristan A. [4 ]
Barbaric, Ivana [1 ,2 ]
机构
[1] Univ Sheffield, Dept Biomed Sci, Western Bank, Sheffield S10 2TN, S Yorkshire, England
[2] Univ Sheffield, Neurosci Inst, Western Bank, Sheffield S10 2TN, S Yorkshire, England
[3] Univ Sheffield, Dept Automat Control & Syst Engn, Mappin St, Sheffield S1 3JD, S Yorkshire, England
[4] Imperial Coll London, Imperial Ctr Translat & Expt Med, Natl Heart & Lung Inst, Hammersmith Hosp Campus,Du Cane Rd, London W12 0NN, England
基金
英国生物技术与生命科学研究理事会; 英国医学研究理事会;
关键词
GROWTH; DIFFERENTIATION; ANTIBODY; CULTURE; DRIVES; RAS; DERIVATION; EXPRESSION; 20Q11.21; ANTIGENS;
D O I
10.1016/j.devcel.2021.07.019
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
引用
收藏
页码:2455 / +
页数:26
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