Stavish, D., Price, C.J., Gelezauskaite, G. et al. (19 more authors) (2024) Feeder-free culture of human pluripotent stem cells drives MDM4-mediated gain of chromosome 1q. Stem Cell Reports, 19 (8). pp. 1217-1232. ISSN 2213-6711
Abstract
Culture-acquired variants in human pluripotent stem cells (hPSCs) hinder their applications in research and clinic. However, the mechanisms that underpin selection of variants remain unclear. Here, through analysis of comprehensive karyotyping datasets from over 23,000 hPSC cultures of more than 1,500 lines, we explored how culture conditions shape variant selection. Strikingly, we identified an association of chromosome 1q gains with feeder-free cultures and noted a rise in its prevalence in recent years, coinciding with increased usage of feeder-free regimens. Competition experiments of multiple isogenic lines with and without a chromosome 1q gain confirmed that 1q variants have an advantage in feeder-free (E8/vitronectin), but not feeder-based, culture. Mechanistically, we show that overexpression of MDM4, located on chromosome 1q, drives variants’ advantage in E8/vitronectin by alleviating genome damage-induced apoptosis, which is lower in feeder-based conditions. Our study explains condition-dependent patterns of hPSC aberrations and offers insights into the mechanisms of variant selection.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2024 The Authors. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licence (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
Keywords: | MDM4; culture conditions; genetic changes; genome damage; human pluripotent stem cells; Humans; Chromosomes, Human, Pair 1; Pluripotent Stem Cells; Cell Cycle Proteins; Proto-Oncogene Proteins; Cell Culture Techniques; Apoptosis; Feeder Cells; Cell Line; Cells, Cultured |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Science (Sheffield) > School of Biosciences (Sheffield) |
Funding Information: | Funder Grant number MEDICAL RESEARCH COUNCIL MR/R015724/1 MEDICAL RESEARCH COUNCIL MR/X000028/1 MEDICAL RESEARCH COUNCIL MR/X007979/1 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 24 Mar 2025 11:30 |
Last Modified: | 24 Mar 2025 11:30 |
Published Version: | https://doi.org/10.1016/j.stemcr.2024.06.003 |
Status: | Published |
Publisher: | Elsevier BV |
Refereed: | Yes |
Identification Number: | 10.1016/j.stemcr.2024.06.003 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:224753 |