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The mutational impact of culturing human pluripotent and adult stem cells

Kuijk, Ewart, Jager, Myrthe, van der Roest, Bastiaan, Locati, Mauro D., Van Hoeck, Arne, Korzelius, Jerome, Janssen, Roel, Besselink, Nicolle, Boymans, Sander, van Boxtel, Ruben, and others. (2020) The mutational impact of culturing human pluripotent and adult stem cells. Nature Communications, 11 (1). E-ISSN 2041-1723. (doi:10.1038/s41467-020-16323-4) (KAR id:81480)

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http://dx.doi.org/10.1038/s41467-020-16323-4

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.

Item Type: Article
DOI/Identification number: 10.1038/s41467-020-16323-4
Uncontrolled keywords: stem cells, organoid culture, mutation frequency, oxidative stress
Subjects: Q Science > QH Natural history > QH426 Genetics
Q Science > QH Natural history > QH581.2 Cell Biology
Q Science > QL Zoology
Divisions: Faculties > Sciences > School of Biosciences > Cell & Developmental Biology Group
Depositing User: Jerome Korzelius
Date Deposited: 01 Jun 2020 13:59 UTC
Last Modified: 03 Jun 2020 03:12 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/81480 (The current URI for this page, for reference purposes)
Korzelius, Jerome: https://orcid.org/0000-0002-8443-0192
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