Molecular and phenotypic blueprint of human hematopoiesis links proliferation stress to stem cell aging

Hematopoietic stem/progenitor cell (HSPC) aging has been associated with myeloid skewing, reduced clonal output, and impaired regenerative capacity, but quantitative immunophenotypic and functional analysis across human aging is lacking. Here, we provide a comprehensive phenotypic, transcriptional, and functional dissection of human hematopoiesis across the lifespan. Although primitive hematopoietic stem cell (HSC) numbers were stable during aging, overall cellularity was reduced, especially for erythroid and lymphoid lineages. Notably, HSPC from aged individuals had similar repopulating frequency of younger counterparts in primary and secondary xenografts; yet aged HSC displayed impaired differentiation capacity, changes in chromatin accessibility, dysregulation of cell cycle, and a reduced capacity to counteract activation-induced proliferative stress with concomitant accumulation of DNA damage and senescence-like features upon xenotransplantation. This age-associated phenotypic and functional decline was recapitulated by enforcing proliferative stress in vivo on human HSPC. Overall, our work sheds light on dysregulated responses to activation-induced proliferation underlying HSPC aging and establishes xenotransplantation-based models as suitable for studying age-associated hematopoietic defects.