Molecular mechanisms underlying replicative stress and genome damage in pluripotent stem cells

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Pluripotent stem cells (PSCs) in the early embryo give rise to all ofthe somatic cells in the body. Maintenance of the genetic integrity of PSCs isessential for preventing genetic defects to be passed onto multiple progeny cells,which would be detrimental for a developing embryo. When placed underappropriate culture conditions, PSCs retain the ability to give rise to differentiatedcells from all three embryonic germ layers, whilst acquiring the ability to self-renew extensively and thus provide an excellent, genetically normal modelsystem to investigate mechanisms that control genome integrity. We and othershave previously shown that PSCs acquire non-random genetic changes uponprolonged culture. However, the molecular mechanisms underlying theiracquisition remain poorly understood. To this end, our project will determine thecontribution of different genome damage mechanisms to the common geneticchanges we observe. We will also elucidate how extrinsic environment(specifically, culture medium composition) enhance or diminish these damagemechanisms. Our previous data has shown that growing cells in different culturemedia and environmental conditions significantly alters their mutation rates.Work from other groups highlighted albumin as a key component of the medium,necessary for stabilizing small molecules and ions and scavenging free radicalsthat could be harmful for macromolecules, particularly the DNA. Hence, incollaboration with our industrial partner Albumedix, who specializes inrecombinant albumin production, we will determine the contribution of intrinsicmechanisms and niche conditions on genome damage of PSCs.