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Culture-acquired genetic changes in human pluripotent stem cells: implications for basic research and regenerative medicine

I Barbaric(1)

1:University of Sheffield

Human pluripotent stem cells are subject to mutations in vitro and in the presence of selection pressures, the variants with genetic changes that allow for improved growth outcompete their neighbours and overtake the culture. The commonly observed genetic changes in hPSCs are non-random and involve gains of (parts of) chromosomes 1, 12, 17, 20 and X, indicating that genes within these regions confer selective advantage to mutant cells. Mutations that arise in hPSCs during in vitro culture can affect their behaviour and confound experimental results. For example, variant cells often show signs of neoplastic progression, including reduced apoptosis, growth-factor independence and higher cloning efficiency. Genetic changes can also affect the propensity of hPSCs to differentiate. Altered patterns of differentiation caused by accrued genetic changes may significantly affect the use of such cell lines in applications that require the production of differentiated derivatives. With hPSC derivatives entering the clinical trials, a possibility that genetic changes may confer malignant properties to hPSCs or their differentiated progeny is a major cause of regulatory concern. In our work we are elucidating the molecular mechanisms that underlie the maintenance of the integrity of the hPSC genome, and how disruption of these mechanisms can lead to undesired genetic changes.

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