Cellular aging of hematopoietic stem cells in physiology and disease.

Human Hematopoietic Stem and Progenitor Cells (HSPC) serve as a lifelong reservoir for mature blood cells. Accumulation of DNA damage in HSPC is a contributing factor to aging and bone marrow failure syndromes. Similarly to what has been observed during aging, we discovered that repeated activation of human HSPC out of their quiescence state for HSPC-based ex-vivo gene therapy applications leads to DNA damage and elicits the DNA damage response (DDR) likely as a consequence of exacerbated DNA replication stress. Yet, we have just scratched the surface of still unexplored molecular mechanisms governing the biological response of HSPC to stress and potentially hampering the fitness of this primitive cell compartment. Here, we seek to identify the molecular determinants of HSPC dysfunctions in two clinically relevant settings: genetic engineering strategies and during physiological or premature aging with the final long-term goal to mitigate detrimental cellular responses for more effective hematopoietic reconstitution upon transplantation. Successful completion of the project will unveil a new set of mechanisms controlling the human HSPC biology and open novel scientific horizons for HSPC-based translational applications.