The mutational impact of culturing human pluripotent and adult stem cells

Ewart Kuijk (), Myrthe Jager, Bastiaan Roest, Mauro D. Locati, Arne Hoeck, Jerome Korzelius, Roel Janssen, Nicolle Besselink, Sander Boymans, Ruben Boxtel and Edwin Cuppen ()
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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

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-16323-4

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