3164 – HOXB5 CONFERS INCREASED STRESS TOLERANCE AND MAINTENANCE OF SELF-RENEWAL TO THE HEMATOPOIETIC STEM CELLS

Self-renewal and multipotency are essential and defining features of the hematopoietic stem cell (HSC). It has been previously suggested that a self-renewal gradient exists within the classic immunophenotypic HSC compartment (Lin-c-Kit+Sca-1+CD150+CD34-/loFlk2-: pHSCs). However, we have yet to explain the selective pressure for this functional heterogeneity nor the mechanism for how this heterogeneity is regulated. Using our Hoxb5 reporter mouse line, we previously demonstrated the ability to distinguish between the long-term (LT) and short-term (ST) HSCs (as Hoxb5+ and Hoxb5- pHSCs respectively), with the former exhibiting a higher self-renewal capacity. In our current studies, we demonstrate that self-renewal is impacted by tolerance to varying degrees of replication stress, resulting in this measured self-renewal heterogeneity. By isolating Hoxb5+ and Hoxb5- pHSCs, we demonstrate that Hoxb5- pHSCs quickly lose self-renewal capacity and are exhausted under various high stress conditions, including transplantation. However, under low stress conditions they can maintain their capacity for self-renewal. Furthermore, we show that ectopic Hoxb5 expression is sufficient to confer stress tolerance against loss of self-renewal to Hoxb5- pHSCs and can alter the cell fate of ST-HSCs to that of LT-HSCs. Therefore, Hoxb5 expression may not simply be a marker of increased stress tolerance but may also serve as a fail-safe system to protect the HSC compartment from exhaustion over an organism's lifespan.