Genetically variant human pluripotent stem cells selectively eliminate wild-type counterparts through YAP-mediated cell competition
| Autor: | Ben A. Stevenson, Samantha Sargeant, Joanne Lacey, Ivana Barbaric, Tristan A. Rodriguez, Paul J. Gokhale, Christopher J. Price, Dylan Stavish |
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| Přispěvatelé: | Medical Research Council (MRC), Biotechnology and Biological Sciences Research Council (BBSRC) |
| Rok vydání: | 2021 |
| Předmět: |
Pluripotent Stem Cells
EXPRESSION Cytoplasm Induced Pluripotent Stem Cells Cell Biology Regenerative medicine Article ANTIGENS culture-acquired variants General Biochemistry Genetics and Molecular Biology CULTURE medicine Humans human pluripotent stem cells cell competition Induced pluripotent stem cell Molecular Biology Cells Cultured 11 Medical and Health Sciences Adaptor Proteins Signal Transducing Cell Proliferation Science & Technology Wild type YAP-Signaling Proteins Cell Differentiation Cell Biology 06 Biological Sciences Phenotype Cell biology DIFFERENTIATION DERIVATION medicine.anatomical_structure ANTIBODY DRIVES Apoptosis GROWTH 20Q11.21 YAP Life Sciences & Biomedicine Nuclear localization sequence Transcription Factors RAS Developmental Biology |
| Zdroj: | 2470.e10 Developmental Cell |
| ISSN: | 1534-5807 |
| Popis: | Summary 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. Graphical abstract Highlights • Genetically variant human pluripotent stem cells (hPSCs) eliminate wild-type cells • Mechanical cues mediate competitive interactions of wild-type and variant hPSCs • Mechanotransducer YAP is a key mediator of cell competition in hPSC cultures • Cell competition allows the fast overtake of cultures by variant hPSCs Price et al. identify competitive interactions that enhance selective advantage of genetically variant human pluripotent stem cells (hPSCs). In the presence of faster-growing variant hPSCs, wild-type cells sequester yes-associated protein (YAP) in the cytoplasm and undergo apoptosis. Neighboring variant cells retain nuclear YAP, remaining proliferative. Modifying culture conditions reduces competitive advantage of variant hPSCs. |
| Databáze: | OpenAIRE |
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