Low rates of mutation in clinical grade human pluripotent stem cells under different culture conditions

Oliver Thompson, Ferdinand Meyenn, Zoe Hewitt, John Alexander, Andrew Wood, Richard Weightman, Sian Gregory, Felix Krueger, Simon Andrews, Ivana Barbaric, Paul J. Gokhale, Harry D. Moore, Wolf Reik, Marta Milo, Serena Nik-Zainal, Kosuke Yusa () and Peter W. Andrews ()
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Oliver Thompson: University of Sheffield, Western Bank
Ferdinand Meyenn: Epigenetics Programme, Babraham Institute
Zoe Hewitt: University of Sheffield, Western Bank
John Alexander: University of Sheffield, Western Bank
Andrew Wood: University of Sheffield, Western Bank
Richard Weightman: University of Sheffield, Western Bank
Sian Gregory: University of Sheffield, Western Bank
Felix Krueger: Bioinformatics Group, Babraham Institute
Simon Andrews: Bioinformatics Group, Babraham Institute
Ivana Barbaric: University of Sheffield, Western Bank
Paul J. Gokhale: University of Sheffield, Western Bank
Harry D. Moore: University of Sheffield, Western Bank
Wolf Reik: Epigenetics Programme, Babraham Institute
Marta Milo: University of Sheffield, Western Bank
Serena Nik-Zainal: Wellcome Genome Campus, Hinxton
Kosuke Yusa: Wellcome Genome Campus, Hinxton
Peter W. Andrews: University of Sheffield, Western Bank

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract The occurrence of repetitive genomic changes that provide a selective growth advantage in pluripotent stem cells is of concern for their clinical application. However, the effect of different culture conditions on the underlying mutation rate is unknown. Here we show that the mutation rate in two human embryonic stem cell lines derived and banked for clinical application is low and not substantially affected by culture with Rho Kinase inhibitor, commonly used in their routine maintenance. However, the mutation rate is reduced by >50% in cells cultured under 5% oxygen, when we also found alterations in imprint methylation and reversible DNA hypomethylation. Mutations are evenly distributed across the chromosomes, except for a slight increase on the X-chromosome, and an elevation in intergenic regions suggesting that chromatin structure may affect mutation rate. Overall the results suggest that pluripotent stem cells are not subject to unusually high rates of genetic or epigenetic alterations.

Date: 2020
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DOI: 10.1038/s41467-020-15271-3

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