Mouse lt-hsc single cells - Aging of hematopoietic stem cells is driven by regional specialization of marrow macrophages

The human aged hematopoietic system is prone to dysfunction and clonal selection. Aged hematopoietic stem cells (HSCs) have well-defined characteristics, but the contribution of the bone marrow microenvironment (BMME) to HSC ageing is unclear. We identify age-dependent changes in bone-associated (BA) and marrow-associated (MA) cell populations in murine and human marrow, where only aged MA cells induce aged HSC characteristics. MA aged macrophages (Mφs) could impart aged characteristics to both HSC and BMME populations, and demonstrated decreased ability to engulf senescent neutrophils. Moreover, removal of Mφs from young mice rapidly induced aged HSC characteristics. Interleukin-1β (IL-1β), a cytokine that is restrained when Mφs engulf apoptotic cells, was a key mediator of microenvironmental HSC aging. These data define a previously unknown role for aged MA Mφs to orchestrate BMME and HSC changes. Mφs and IL-1β may therefore represent novel targets for preventing or reversing hematopoietic defects due to advanced age.