DNA repair mechanisms and cellular reprogramming: Criteria for the successful generation of human induced pluripotent stem cells and in vitro disease modelling

Abstract

Maintenance of genomic integrity is an important aspect of stem cell function All stem cells, whether they are pluripotent or multipotent tissue-specific cells, need to be able to eliminate genomic mutations if they threaten the ability of the cell to complete its function in vivo. This is of great importance for adult stem cells, the purpose of which is the lifelong repair and regeneration of a specific organ system. It is easy to imagine the potential harm that could accumulate in the haematopoietic system if only a small fraction of the haematopoietic stem cells (HSCs) resident in the endosteal niche of the bone marrow (BM) were allowed to accumulate mutations that altered their ability to generate lymphoid or myeloid lineages. Because the daily requirement for new blood cells is of the order of one billion, damage of this type would soon become apparent, and the patient's health would decline. Important though this is, the impact of mutations occurring in adult life is minor compared to the possible disruptions that could arise if the genome of the early embryo was damaged to the point that embryonic development was restricted. The inner cell mass (ICM) of blastocyst-stage embryos gives rise to every tissue found in the adult but consists of a very small number of cells (which can be as few as 12 cells). If a mutation is allowed to persist in any of the ICM cells, it will be transferred to the tissues and organs that arise from that cell and could have a profound effect on organ function. Therefore, the accumulation of mutations in the ICM must be prevented at all costs.