When good cells go bad: Causes and consequences of aneuploidy in human pluripotent stem cells

Human pluripotent stem cells (hPSCs) represent powerful tools for modelling early human embryogenesis and provide a source of differentiated cells for use in regenerative medicine. The assurance of genetic stability is essential for uses of hPSCs in basic research and regenerative medicine. Nonetheless, hPSCs are known to acquire non-random genetic changes, including recurrent aneuploidies. Some of the acquired genetic aberrations that are associated with the selective growth advantage of variant hPSCs are known to be associated with oncogenesis in other situations, raising the concern that they may also confer tumorigenic or malignant properties on either transplanted differentiated cells or left-over undifferentiated hPSCs. Moreover, genetic changes in hPSCs could also impact basic research because the experimental manipulation of aneuploid hPSCs possessing aberrant proliferation rates or varying differentiation abilities may generate unpredictable results, rendering hPSC-based disease modelling, and developmental studies unreliable.
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 aneuploidy on the behavior of hPSCs in vitro. Our recent work has demonstrated that the dominance of aneuploid hPSCs in mosaic cultures is enhanced through competitive interactions resulting in elimination of wild-type cells, akin to the cell competition behavior described in other cell and developmental models. Understanding of the causes and consequences of aneuploidy in hPSCs will help inform approaches to minimise their occurrence in hPSC cultures destined for clinical or research use. These insights may be also pertinent to assisted conception efforts and may open new therapeutic approaches to target aneuploid cells in cancer.

Learning Objectives:

1. identify the types of genetic changes that commonly occur in hPSCs

2. appraise the key issues and challenges that genetic changes in hPSCs represent for regenerative medicine

3. discuss how understanding of the processes of mutation and selection may contribute to minimising the appearance of genetic variants