Bone marrow adipocytes fuel hematopoietic regeneration via fatty acid release Free

In adulthood, hematopoietic stem cells (HSCs) reside in the bone marrow niche, where they are maintained by growth factors such as stem cell factor (SCF) produced by niche cells, including Leptin Receptor-expressing (LEPR⁺) stromal cells and endothelial cells. Bone marrow adipocytes, which are progeny of LEPR⁺ cells, also synthesize SCF and other factors that support HSC regeneration. However, the unique metabolic properties of bone marrow adipocytes and their role in hematopoietic regulation remain unclear.We performed single-cell RNA sequencing on murine bone marrow adipocytes and compared them with white and brown adipocytes. Our analysis revealed that bone marrow adipocytes lack thermogenic markers such as uncoupling protein 1 (Ucp1) and exhibit a gene expression profile similar to white adipocytes, suggesting comparable lipolytic capacity. Pharmacologic modulation of bone marrow adipocytes using rosiglitazone (which increases adipocytes) and bisphenol A diglycidyl ether (BADGE, which decreases adipocytes) did not affect steady-state hematopoiesis or HSC frequency and function. However, these treatments significantly impacted hematopoietic regeneration after bone marrow transplantation, with rosiglitazone promoting and BADGE inhibiting recovery. This indicates that while bone marrow adipocytes are dispensable for HSC maintenance and steady-state hematopoiesis, they are crucial for hematopoietic regeneration.Further investigation revealed that sympathetic nerve fibers are essential for efficient adipocyte lipolysis and clearance in the marrow. Denervation via Ngf deletion in LEPR⁺ cells or chemical sympathectomy with 6-hydroxydopamine (6-OHDA) led to increased bone marrow adipocytes and reduced hematopoietic regeneration. Lipidomics and RNA sequencing of hematopoietic stem/progenitor cells (HSPCs) during regeneration showed upregulation of fatty acid (FA) import and oxidation genes, including CD36 and Acaa2. Conditional deletion of these genes in HSCs did not affect steady-state hematopoiesis but significantly impaired regeneration, highlighting the critical role of FA oxidation in HSCs during stress.To identify the source of FA, we generated Lepr-CreER; Pnpla2^fl/fl mice, in which Pnpla2 (encoding adipose triglyceride lipase, ATGL) was conditionally deleted in LEPR⁺ cells and their adipocyte progeny. Following tamoxifen induction, these mice exhibited normal steady-state hematopoiesis but impaired regeneration, with reduced FA levels in HSPCs. This suggests that FA released by LEPR⁺ cells and their progeny is essential for HSC regeneration. Next, we developed a dual recombinase-mediated intersectional genetic approach to conditionally delete Pnpla2 only in bone marrow adipocytes, but not in LEPR⁺ cells or adipocytes in other fat depots, using Lepr^DreER/+; Cidec^CreER-RSR/+; Pnpla2^fl/fl mice. Lepr^DreER/+; Cidec^CreER-RSR/+; Pnpla2^fl/fl mice recapitulated the phenotypes observed in Lepr-CreER; Pnpla2^fl/fl mice and in mice subjected to bone marrow denervation. Specifically, steady-state hematopoiesis remained unaffected, whereas hematopoietic regeneration was significantly impaired. These data further highlighted the critical role of bone marrow adipocytes during regeneration.Our findings establish that bone marrow adipocytes represent a metabolically distinct depot whose rapid, sympathetic-driven lipolysis mobilizes local fatty acids to fuel HSC regeneration after injury. Targeting this marrow-fat axis with pharmacologic or genetic strategies that enhance adipocyte lipolysis offers a novel approach to accelerate engraftment and reduce morbidity following bone-marrow transplantation.