Aging Hematopoiesis: Functional Insights and Prospects for Rejuvenation

Aging exerts profound effects on the hematopoietic system, leading to a loss of homeostatic control and reduced regenerative capacity. Clinical consequences of these changes include anemia, compromised immune function and an increased prevalence of myeloid disorders among the elderlies. A growing body of evidence suggests that defects at the stem and progenitor cell levels contribute to many of the hematopoietic aging phenotypes. In this thesis, I examined the function of hematopoietic stem cells (HSCs), the source of all mature blood cells, during adulthood and upon aging. By using an in vivo lineage tracing mouse system and high-throughput RNA profiling, I demonstrate a gradual decline in HSC multilineage differentiation capacity, with the most significant reduction in their lymphoid output. Decreased lymphopoiesis could be traced back to the primitive lymphoid progenitor subset, MPP Ly-I, revealing defects in the transition of HSC to these cells. To address age-related HSC decline, we employed a recently developed HSC culture system which allows for activation and robust self-renewal of input HSCs. Although ex vivo culture of aged HSCs failed to correct their in vivo function, we nevertheless observed that the aged HSC pool contains rare multilineage/lymphoid competent clones, which makes these promising candidates for strategies aimed at hematopoietic rejuvenation. In parallel, we investigated molecular changes associated with age-related HSC decline by re-analyzing existing transcriptomic data on HSC aging. We discovered only partial overlap in HSC aging signatures between prior studies, which prompted us to address the potential causes for such variation. We found that cell isolation procedure and sample handling both impact on the molecular profiles of the cells. In particular, incubation of cells at elevated temperature triggered a stress signature which overrides the genuine molecular profile of the cells. Notably, this stress response was age-independent, but with implications for prior interpretations of HSC aging mechanisms. Finally, given the intrinsic nature of many of the age-associated HSC phenotypes, we explored the potential for cell replacement therapy through young HSC transplantation to reinstate a more youthful hematopoietic function in older subjects. While several key parameters needed to be optimized, including non-invasive conditioning regimen prior to transplantation and HSC transplant doses, we demonstrated successful integration of young HSCs in aged recipients. Importantly, these young cells largely retained their function in the aged environment, contributing effectively to hematopoietic output, and particularly to mature lymphocytes. Hence, this data suggest that non-invasive transplantation of young HSCs holds promise as a potential strategy to alleviate some hematopoietic aging phenotypes. Collectively, this thesis work provides new insights into hematopoietic aging and set the stage for more comprehensive investigations of HSC transplantation as a potential approach for hematopoietic rejuvenation.