Survival of the fittest: The cause and consequences of genetic changes in human pluripotent stem cells
Human pluripotent stem cells (hPSCs) have the ability to self-renew indefinitely and differentiate into all types of tissue in the body, providing a potentially unlimited source of differentiated cell types for use in regenerative medicine, disease modelling and drug discovery. The use of hPSCs in these applications will necessitate the maintenance of large numbers of undifferentiated, genetically stable cells. Human PSCs are subject to mutations in vitro and in the presence of selection pressures, the variants with mutations 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 and 20, 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 mutations may significantly affect the use of such cell lines in applications that require the production of differentiated derivatives. Further, the commonly observed mutations in hPSCs are also frequent in human embryonal carcinoma cells, the stem cells of germ cell tumours teratocarcinomas. 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. We are also studying the functional effects of genetic changes on the behavior of hPSCs in vitro. Investigating the causes and consequences of genetic changes in hPSCs will help inform approaches to minimise their occurrence in hPSC cultures.
Ivana Barbaric completed her DPhil at the University of Oxford in 2006. She then joined Professor Peter Andrews’ group at the University of Sheffield to study the mechanisms that underlie human pluripotent stem cell fate. In 2013, Ivana was awarded a Wellcome Trust discipline hopping fellowship to engineer controlled microenvironments in order to understand mechanical and chemical cues influencing stem cell fate. She was appointed to a Group Leader position at the Centre for Stem Cell Biology, Sheffield in 2014. Her research is focused on investigating the causes and consequences of genetic changes in human pluripotent stem cells (hPSCs), and studying how signals from the stem cells microenvironment affect their fate decisions and patterning. Her group is also using human pluripotent stem cells for disease modelling and drug discovery.