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

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OA Location

https://reader.elsevier.com/reader/sd/pii/S153458072100602X?token=C7EEE2740B42E1215DF924DCC52F7040EAB008CF253C2D76C85C34FE80FDBEBD5270E70FF5EC8B2F3C394746E2E311A0&originRegion=eu-west-1&originCreation=20210827081735

Author(s)

Price, Christopher J

Stavish, Dylan

Gokhale, Paul J

Stevenson, Ben A

Sargeant, Samantha

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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.

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Date Issued

2021-09-13

Date Acceptance

2021-07-26

Citation

Developmental Cell, 2021, 56 (17), pp.2455-2470.e10

URI

http://hdl.handle.net/10044/1/91295

URL

https://www.sciencedirect.com/science/article/pii/S153458072100602X?via%3Dihub

DOI

https://www.dx.doi.org/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/)

License URL

http://creativecommons.org/licenses/by/4.0/

Sponsor

Medical Research Council (MRC)

Medical Research Council (MRC)

Biotechnology and Biological Sciences Research Council (BBSRC)

Biotechnology and Biological Sciences Research Council (BBSRC)

Identifier

https://www.ncbi.nlm.nih.gov/pubmed/34407428

PII: S1534-5807(21)00602-X

Grant Number

MR/N009371/1

MR/P018467/1

BB/S008284/1

EP/V520354/1

Subjects

YAP

cell competition

culture-acquired variants

human pluripotent stem cells

Publication Status

Published

Coverage Spatial

United States

Date Publish Online

2021-08-17