The study identifies nestin-expressing mesenchymal stem cells (MSCs) as a critical component of the hematopoietic stem cell (HSC) niche in the bone marrow. These nestin+ MSCs are spatially associated with HSCs and adrenergic nerve fibers, and they highly express genes essential for HSC maintenance. The nestin+ cells form multipotent, self-renewing mesenspheres and contribute to osteochondral lineages in vivo. They are quiescent and metabolically active, regulated by both parathyroid hormone and the sympathetic nervous system. Depletion of nestin+ cells reduces HSC content and impairs HSC homing, highlighting their essential role in maintaining the HSC niche. This work reconciles previous divergent views on the cellular components of the HSC niche, suggesting a unique niche composed of MSC-HSC pairings.The study identifies nestin-expressing mesenchymal stem cells (MSCs) as a critical component of the hematopoietic stem cell (HSC) niche in the bone marrow. These nestin+ MSCs are spatially associated with HSCs and adrenergic nerve fibers, and they highly express genes essential for HSC maintenance. The nestin+ cells form multipotent, self-renewing mesenspheres and contribute to osteochondral lineages in vivo. They are quiescent and metabolically active, regulated by both parathyroid hormone and the sympathetic nervous system. Depletion of nestin+ cells reduces HSC content and impairs HSC homing, highlighting their essential role in maintaining the HSC niche. This work reconciles previous divergent views on the cellular components of the HSC niche, suggesting a unique niche composed of MSC-HSC pairings.