Aging of Hematopoietic Stem Cells is Driven by Regional Specialization of Marrow Macrophages

While hematopoietic stem cells (HSCs)-intrinsic effects of aging have been explored, less is known about how HSC support is altered by the aged bone marrow microenvironment (BMME). To assess the role of the BMME in HSC aging, we compared the BMME in young (6-12 weeks) and aged (20-24 months) male mice and young (<50 years old; YO) and aged (>50 YO) human volunteers. Aged mice had remodeling of the BMME, with expansion of the marrow cavity and vascular volume compared to young mice. BMME constituents were redistributed within two distinct anatomic regions, namely endosteal bone-associated (BA) and marrow-associated (MA) cells. BA cells in aged mice contained fewer phenotypic mesenchymal/osteoblastic progenitors, with reduction in their ability to constitute colony forming units (CFUs). CFU loss was also observed in aged human volunteers. Aged murine MA had significant expansion of dysfunctional mesenchymal stem cells (MSCs) and activated macrophages (MΦ). Increased MΦ were also detected in aged human marrows.