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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



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