Author:
Lettera Emanuele,Scala Serena,Basso-Ricci Luca,Tavella Teresa,Volpe Lucrezia della,Furno Elena Lo,Kaufmann Kerstin B.,Garcia-Prat Laura,Quaranta Pamela,Hernandez Raisa Jofra,Murison Alex,Giannetti Kety,Aguilar-Navarro Alicia G.,Beretta Stefano,Conti Anastasia,Farina Giacomo,Flores-Figueroa Eugenia,Conte Pietro,Ometti Marco,Merelli Ivan,Xie Stephanie Z.,Aiuti Alessandro,Micco Raffaella Di
Abstract
AbstractHematopoietic stem/progenitor cell (HSPC) aging studies have 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 HSPC numbers were stable during aging, overall cellularity was reduced, especially for erythroid and lymphoid lineages. Notably, HSPC from aged individuals had superior repopulating frequency than younger counterparts in xenografts; yet aged HSPC displayed epigenetic dysregulation of cell cycle, inflammatory signatures, and a reduced capacity to counteract activation-induced proliferative stress with concomitant accumulation of DNA damage and senescence-like features upon xenotransplantation. This phenotype was recapitulated by enforcing proliferative stressin vivoon cord blood (CB) HSPC. Overall, our work sheds light on dysregulated responses to activation-induced proliferation underlying HSPC aging and establishes CB xenotransplantation-based models as suitable for studying age-associated hematopoietic defects.
Publisher
Cold Spring Harbor Laboratory