Aging Decline of LEPR+ HSCs

Leptin receptor (LEPR) identifies a subpopulation of hematopoietic stem cells (HSCs) with high repopulating potential. In this study, we demonstrated that LEPR-expressing HSCs while exhibiting significantly higher engrafting potential and self-renewing capacity in young mice showed early age-associated decline in these functions as compared to the LEPR- HSCs. LEPR+ HSCs have transcriptomic profiles significantly different from LEPR- HSCs in young mouse bone marrow, but middle-aged HSCs do not have distinct transcriptomic profiles based on LEPR status. The age-related phenotypes were associated with a proinflammatory transcriptomic profile at baseline in young LEPR+ HSCs, which was further exacerbated by age. In contrast, LEPR- HSCs did not show age-associated functional impairment at the ages tested. This suggested that subsets of HSCs are susceptible to age-related decline in function at varying ages and that LEPR+ HSCs are a potential target for early cellular therapeutic interventions in delaying the detrimental effects of aging in hematopoiesis. Overall design: Differential gene expression of young and middle-aged murine HSCs based on LEPR status. Comparisons performed were: young LEPR+ HSCs vs young LEPR- HSCS; middle-aged LEPR+ HSCs vs middle-aged LEPR- HSCs; young LEPR+ HSCs vs middle-aged LEPR+ HSCs; young LEPR- HSCs vs middle-aged LEPR- HSCs.