Aberrant engagement of P-selectin drives hematopoietic stem cell aging

During aging, hematopoietic stem cell (HSC) function progressively declines which can lead to reduced blood cell production and regeneration, impaired lymphoid cell production and ineffective erythropoiesis. In this study, we uncovered that during aging the cell surface presentation of the type-1 transmembrane protein P-selectin (CD62P, encoded by Selp) increases in a large fraction of HSCs. Notably, expression of P-selectin molecularly and functionally dichotomized the aging HSC pool; stem cells presenting with high abundance of P-selectin were hallmarked by aging-associated gene expression programs and reduced repopulation upon regenerative stress. Overexpression of Selp in young HSCs was sufficient to impair long-term reconstitution potential and repress erythropoiesis. Moreover, IL-1β, which is chronically elevated in the aged bone marrow, triggered Selp expression in HSCs. The aged transcriptome, including Selp, was largely restored when aged HSCs were transplanted to young mice. Mechanistically, we uncovered that appropriate stimulation of P-selectin by its primary ligand, P-selectin glycoprotein ligand-1 (PSGL-1), suppressed aging-associated gene expression and reversely, lack of P-selectin signaling led to HSC premature aging. Collectively, our study uncovered a novel functional role of P-selectin engagement in regulating HSC regeneration and driving stem cell aging when perturbed.