Gains of 20q11.21 in human pluripotent stem cells: Insights from cancer research

Krivec, Nuša; Ghosh, Manjusha S.; Spits, Claudia

doi:10.1016/j.stemcr.2023.11.013

Stem Cell Reports

2024

DOI: 10.1016/j.stemcr.2023.11.013

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Gains of 20q11.21 in human pluripotent stem cells: Insights from cancer research

Nuša Krivec,

Manjusha S. Ghosh,

Claudia Spits

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2024

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Cited by 2 publications

References 171 publications

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Culture‐acquired genetic variation in human pluripotent stem cells: Twenty years on

Vales,

Barbaric

2024

BioEssays

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Genetic changes arising in human pluripotent stem cells (hPSC) upon culture may bestow unwanted or detrimental phenotypes to cells, thus potentially impacting on the applications of hPSCs for clinical use and basic research. In the 20 years since the first report of culture‐acquired genetic aberrations in hPSCs, a characteristic spectrum of recurrent aberrations has emerged. The preponderance of such aberrations implies that they provide a selective growth advantage to hPSCs upon expansion. However, understanding the consequences of culture‐acquired variants for specific applications in cell therapy or research has been more elusive. The rapid progress of hPSC‐based therapies to clinics is galvanizing the field to address this uncertainty and provide definitive ways both for risk assessment of variants and reducing their prevalence in culture. Here, we aim to provide a timely update on almost 20 years of research on this fascinating, but a still unresolved and concerning, phenomenon.

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Culture‐acquired genetic variation in human pluripotent stem cells: Twenty years on

Vales,

Barbaric

2024

BioEssays

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Longitudinal analysis of genetic and epigenetic changes in human pluripotent stem cells in the landscape of culture-induced abnormality

Kim,

Kang,

Kweon

et al. 2024

Exp Mol Med

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Human embryonic stem cells (hESCs) are naturally equipped to maintain genome integrity to minimize genetic mutations during early embryo development. However, genetic aberration risks and subsequent cellular changes in hESCs during in vitro culture pose a significant threat to stem cell therapy. While a few studies have reported specific somatic mutations and copy number variations (CNVs), the molecular mechanisms underlying the acquisition of ‘culture-adapted phenotypes’ by hESCs are largely unknown. Therefore, we conducted comprehensive genomic, single-cell transcriptomic, and single-cell ATAC-seq analyses of an isogenic hESC model displaying definitive ‘culture-adapted phenotypes’. We found that hESCs lacking TP53, in which loss-of-function mutations were identified in human pluripotent stem cells (hPSCs), presented a surge in somatic mutations. Notably, hPSCs with a copy number gain of 20q11.21 during early passage did not present ‘culture-adapted phenotypes’ or BCL2L1 induction. Single-cell RNA-seq and ATAC-seq analyses revealed active transcriptional regulation at the 20q11.21 locus. Furthermore, the induction of BCL2L1 and TPX2 to trigger ‘culture-adapted phenotypes’ was associated with epigenetic changes facilitating TEA domain (TEAD) binding. These results suggest that 20q11.21 copy number gain and additional epigenetic changes are necessary for expressing ‘culture-adapted phenotypes’ by activating gene transcription at this specific locus.

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Gains of 20q11.21 in human pluripotent stem cells: Insights from cancer research

Cited by 2 publications

References 171 publications

Culture‐acquired genetic variation in human pluripotent stem cells: Twenty years on

Culture‐acquired genetic variation in human pluripotent stem cells: Twenty years on

Longitudinal analysis of genetic and epigenetic changes in human pluripotent stem cells in the landscape of culture-induced abnormality

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