Mouse CD11b+ macrophages - 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 (Mfs) could impart aged characteristics to both HSC and BMME populations, and demonstrated decreased ability to engulf senescent neutrophils. Moreover, removal of Mfs from young mice rapidly induced aged HSC characteristics. Interleukin-1ß (IL-1ß), a cytokine that is restrained when Mfs engulf apoptotic cells, was a key mediator of microenvironmental HSC aging. These data define a previously unknown role for aged MA Mfs to orchestrate BMME and HSC changes. Mfs and IL-1ß may therefore represent novel targets for preventing or reversing hematopoietic defects due to advanced age. Overall design: mRNA profiles of CD11b+ macrophages from bone marrow and bone associated cells were generated from three individual mice by Illumina HiSeq 2500 sequencing.