Schematic of how SBDS deficiency in the Mx1^CreSBDS^Exc model impacts BM niche cell composition and gene expression in response to myeloablative irradiation, leading to impaired niche capacity to engraft donor HSC after HSCT. Our studies support a model by which Sbds knockdown in Mx1-inducible osteolineage niche cells impairs donor HSC engraftment after TBI. SBDS deficiency in osteoprogenitors causes ribosomal dysfunction, p53 pathway activation, and cell cycle arrest, which impairs the ability of these OCs to proliferate in response to IGF-1 and other growth factor signals after TBI and, consequently, to support donor hematopoiesis. Because of cell intrinsic or extrinsic mechanisms, SBDS deficiency in niche cells also increases adipocytes and decreases EC survival in the BM microenvironment after TBI, both of which may impair donor engraftment after HSCT. Decreased osteoprogenitor-derived CXCL12 and endothelial P-selectin expression may limit HSC homing and lodgment within BM niches after TBI. Elevation of CCL3 and endothelial E-selectin drives recruitment of inflammatory macrophages after TBI. The resulting proinflammatory environment may further disrupt engraftment and maintenance of donor HSPC.