P-selectin identifies molecularly and functionally aged long-term hematopoietic stem cells in Mus musculus C57BL/6 female mice

Aged hematopoietic stem cells (HSCs) display myeloid-biased differentiation and reduced regenerative potential. In this study, we uncover that P-selectin (Selp) marks a subset of aged HSCs with reduced repopulation capacity. This population of HSCs expresses a prominent aging transcriptome. Overexpression of Selp in young HSCs impaired long-term reconstitution potential and repressed erythropoiesis. We show that IL-1β is elevated in aged bone marrow and administration of IL-1β induces expression of Selp and other aging-associated genes in HSCs. Finally, we demonstrate that transplantation of aged HSCs into young recipients restores a young-like transcriptome, specifically by repressing pro-inflammatory pathways, highlighting the important role of the bone marrow microenvironment in HSC aging. Pre-transplant: 5000 Selp low HSCs (lineage negative, Sca-1+ c-Kit+ CD48- CD150+ Selp low) and 5000 Selp high HSCs (lineage negative, Sca-1+ c-Kit+ CD48- CD150+ Selp high), sorted from 4 old (>24 months) mice, were used for RNA-seq. Post-transplant: 1000 old Selp low and Selp high HSCs were transplanted to lethally irradiated young recipients (10-16 weeks), respectively. After 16 weeks, 5000 Selp low derived HSCs (CD45.2+ lineage negative, Sca-1+ c-Kit+ CD48- CD150+) and Selp high derived HSCs (CD45.2+ lineage negative, Sca-1+ c-Kit+ CD48- CD150+), sorted from recipients, were used for RNA-seq.