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Genetically variant human pluripotent stem cells selectively eliminate wild-type counterparts through YAP-mediated cell competition
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Title: | Genetically variant human pluripotent stem cells selectively eliminate wild-type counterparts through YAP-mediated cell competition |
Authors: | Price, CJ Stavish, D Gokhale, PJ Stevenson, BA Sargeant, S Lacey, J Rodriguez, TA Barbaric, I |
Item Type: | Journal Article |
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 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. |
Issue Date: | 13-Sep-2021 |
Date of Acceptance: | 26-Jul-2021 |
URI: | http://hdl.handle.net/10044/1/91295 |
DOI: | 10.1016/j.devcel.2021.07.019 |
ISSN: | 1534-5807 |
Publisher: | Elsevier |
Start Page: | 2455 |
End Page: | 2470.e10 |
Journal / Book Title: | Developmental Cell |
Volume: | 56 |
Issue: | 17 |
Copyright Statement: | ©2021 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) |
Sponsor/Funder: | Medical Research Council (MRC) Medical Research Council (MRC) Biotechnology and Biological Sciences Research Council (BBSRC) Biotechnology and Biological Sciences Research Council (BBSRC) |
Funder's Grant Number: | MR/N009371/1 MR/P018467/1 BB/S008284/1 EP/V520354/1 |
Keywords: | Science & Technology Life Sciences & Biomedicine Cell Biology Developmental Biology GROWTH DIFFERENTIATION ANTIBODY CULTURE DRIVES RAS DERIVATION EXPRESSION 20Q11.21 ANTIGENS YAP cell competition culture-acquired variants human pluripotent stem cells YAP cell competition culture-acquired variants human pluripotent stem cells 06 Biological Sciences 11 Medical and Health Sciences Developmental Biology |
Publication Status: | Published |
Conference Place: | United States |
Open Access location: | https://reader.elsevier.com/reader/sd/pii/S153458072100602X?token=C7EEE2740B42E1215DF924DCC52F7040EAB008CF253C2D76C85C34FE80FDBEBD5270E70FF5EC8B2F3C394746E2E311A0&originRegion=eu-west-1&originCreation=20210827081735 |
Online Publication Date: | 2021-08-17 |
Appears in Collections: | National Heart and Lung Institute Faculty of Medicine |
This item is licensed under a Creative Commons License