Regional Localization within the Bone Marrow Influences the Functional Capacity of Human HSCs

Numerous studies have shown that the bone marrow (BM) niche plays a key role in mouse hematopoietic stem cell (HSC) function and involves contributions from a broad array of cell types. However, the composition and role of the human BM HSC niche have not been investigated. Here, using human bone biopsy specimens, we provide evidence of HSC propensity to localize to endosteal regions of the trabecular bone area (TBA). Through functional xenograft transplantation, we found that human HSCs localizing to the TBA have superior regenerative and self-renewal capacity and are molecularly distinct from those localizing to the long bone area (LBA). In addition, osteoblasts in the TBA possess unique characteristics and express a key network of factors that regulate TBA- versus LBA-localized human HSCs in vivo. Our study reveals that BM localization and architecture play a critical role in defining the functional and molecular properties of human HSCs. [Display omitted] •Human HSCs are preferentially localized to the trabecular bone area•In xenografted mice, human HSCs recapitulate trabecular versus long bone localization•Trabecular versus long bone HSCs have distinct functional and molecular properties•Increased Notch signaling activity in trabecular osteoblasts promotes HSC function Human HSCs that localize preferentially to the trabecular bone region have superior regenerative capacity, suggesting that bone marrow regional localization affects HSC function.