P-selectin delineates conserved functional heterogeneity in early hematopoietic stem cell aging in humans and mice

Vollständiger Abstract

Worum geht es in dieser Arbeit?

Abstract Progressive aging of bone marrow hematopoietic stem cells (HSCs) underlies clonal hematopoiesis and age-associated hematologic disorders. Defining early molecular events driving HSC functional decline is essential for rejuvenation strategies. Here, we identify P-selectin (Selp) as a surface marker that stratifies HSCs into conserved functional and transcriptional states during organismal aging in humans and mice. P-selectin expression increases early during aging and remains elevated in old HSCs. Selp high -HSCs exhibit increased DNA damage and bias towards megakaryocytic/myeloid lineage fate, whereas Selp low -HSCs maintain metabolic integrity, enhanced antioxidant capacity, and reduced myeloid skewing. Transcriptomic analysis revealed that Selp high -HSCs adopt megakaryocytic-primed, pro-inflammatory, and oxidative stress programs, while Selp low -HSCs retain lymphoid-associated and redox-balanced signatures consistent with a more preserved stem-cell state. Further ATAC-seq analysis demonstrates distinct chromatin landscapes with Selp high -HSCs being enriched for inflammatory and platelet-related regulatory elements and CTCF motifs, but Selp low -HSCs displaying accessible ETS-driven networks linked to metabolic fitness and stem cell resilience. Together, these findings uncover conserved heterogeneity during blood stem cell aging and establish P-selectin as an early biomarker and potential therapeutic target to mitigate age-associated hematopoietic decline.