DNA repair mechanisms and cellular reprogramming - criteria for successful generation of human induced pluripotent stem cells and in vitro disease modelling
Abstract
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. For adult stem cells whose purpose is the lifelong repair and regeneration of a specific organ system, this is of great importance. It takes only a little imagination to envisage the potential harm that could accrue 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. The daily requirement for new blood cells is of the order of one billion, so 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 (this 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. The accumulation of mutations in the ICM must be prevented at all costs.
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