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The mutational impact of culturing human pluripotent and adult stem cells

Author

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  • Ewart Kuijk

    (University Medical Center Utrecht, Universiteitsweg 100)

  • Myrthe Jager

    (University Medical Center Utrecht, Universiteitsweg 100)

  • Bastiaan Roest

    (University Medical Center Utrecht, Universiteitsweg 100)

  • Mauro D. Locati

    (University Medical Center Utrecht, Universiteitsweg 100)

  • Arne Hoeck

    (University Medical Center Utrecht, Universiteitsweg 100)

  • Jerome Korzelius

    (Beutenbergstraße 11)

  • Roel Janssen

    (University Medical Center Utrecht, Universiteitsweg 100)

  • Nicolle Besselink

    (University Medical Center Utrecht, Universiteitsweg 100)

  • Sander Boymans

    (University Medical Center Utrecht, Universiteitsweg 100)

  • Ruben Boxtel

    (Heidelberglaan 25, 3584 CS Utrecht)

  • Edwin Cuppen

    (University Medical Center Utrecht, Universiteitsweg 100)

Abstract

Genetic changes acquired during in vitro culture pose a risk for the successful application of stem cells in regenerative medicine. To assess the genetic risks induced by culturing, we determined all mutations in individual human stem cells by whole genome sequencing. Individual pluripotent, intestinal, and liver stem cells accumulate 3.5 ± 0.5, 7.2 ± 1.1 and 8.3 ± 3.6 base substitutions per population doubling, respectively. The annual in vitro mutation accumulation rate of adult stem cells is nearly 40-fold higher than the in vivo mutation accumulation rate. Mutational signature analysis reveals that in vitro induced mutations are caused by oxidative stress. Reducing oxygen tension in culture lowers the mutational load. We use the mutation rates, spectra, and genomic distribution to model the accumulation of oncogenic mutations during typical in vitro expansion, manipulation or screening experiments using human stem cells. Our study provides empirically defined parameters to assess the mutational risk of stem cell based therapies.

Suggested Citation

  • Ewart Kuijk & Myrthe Jager & Bastiaan Roest & Mauro D. Locati & Arne Hoeck & Jerome Korzelius & Roel Janssen & Nicolle Besselink & Sander Boymans & Ruben Boxtel & Edwin Cuppen, 2020. "The mutational impact of culturing human pluripotent and adult stem cells," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16323-4
    DOI: 10.1038/s41467-020-16323-4
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    Cited by:

    1. Daan M. K. Soest & Paulien E. Polderman & Wytze T. F. Toom & Janneke P. Keijer & Markus J. Roosmalen & Tim M. F. Leyten & Johannes Lehmann & Susan Zwakenberg & Sasha Henau & Ruben Boxtel & Boudewijn M, 2024. "Mitochondrial H2O2 release does not directly cause damage to chromosomal DNA," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    2. André Bortolini Silveira & Alexandre Houy & Olivier Ganier & Begüm Özemek & Sandra Vanhuele & Anne Vincent-Salomon & Nathalie Cassoux & Pascale Mariani & Gaelle Pierron & Serge Leyvraz & Damian Rieke , 2024. "Base-excision repair pathway shapes 5-methylcytosine deamination signatures in pan-cancer genomes," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    3. Patricia Gerdes & Sue Mei Lim & Adam D. Ewing & Michael R. Larcombe & Dorothy Chan & Francisco J. Sanchez-Luque & Lucinda Walker & Alexander L. Carleton & Cini James & Anja S. Knaupp & Patricia E. Car, 2022. "Retrotransposon instability dominates the acquired mutation landscape of mouse induced pluripotent stem cells," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    4. Sriram Vijayraghavan & Thomas Blouin & James McCollum & Latarsha Porcher & François Virard & Jiri Zavadil & Carol Feghali-Bostwick & Natalie Saini, 2024. "Widespread mutagenesis and chromosomal instability shape somatic genomes in systemic sclerosis," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    5. Johann-Christoph Jann & Maximilian Mossner & Vladimir Riabov & Eva Altrock & Nanni Schmitt & Johanna Flach & Qingyu Xu & Verena Nowak & Julia Obländer & Iris Palme & Nadine Weimer & Alexander Streuer , 2021. "Bone marrow derived stromal cells from myelodysplastic syndromes are altered but not clonally mutated in vivo," Nature Communications, Nature, vol. 12(1), pages 1-11, December.

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