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

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. Selphigh-HSCs exhibit increased DNA damage and bias towards megakaryocytic/myeloid lineage fate, whereas Selplow-HSCs maintain metabolic integrity, enhanced antioxidant capacity, and reduced myeloid skewing. Transcriptomic analysis revealed that Selphigh-HSCs adopt megakaryocytic-primed, pro-inflammatory, and oxidative stress programs, while Selplow-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 Selphigh-HSCs being enriched for inflammatory and platelet-related regulatory elements and CTCF motifs, but Selplow-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. This study identifies P-selectin (Selp) as an evolutionarily conserved surface marker that captures functional and transcriptomic heterogeneity within the elderly hematopoietic stem cell (HSC) compartment. Early aged HSC pools are stratified by Selp expression levels into functionally divergent populations, driven by separate transcriptional programs and chromatin landscapes. P-selectin marks conserved early aging HSC states in both mice and humans. P-selectin expression stratifies early aged HSCs into more vulnerable Selphigh-state and more resilient Selplow-state. Selp-defined early-aged HSC states are characterised by distinct transcriptional and epigenetic regulatory programs. P-selectin marks conserved early aging HSC states in both mice and humans. P-selectin expression stratifies early aged HSCs into more vulnerable Selphigh-state and more resilient Selplow-state. Selp-defined early-aged HSC states are characterised by distinct transcriptional and epigenetic regulatory programs. P-selectin captures distinct functional and transcriptomic states in aged blood stem cells.