1919-P: Regulation and Function of Bone Marrow Adipocytes in Osteogenesis and Hematopoiesis

In the bone marrow stroma, skeletal stem cells (SSCs) and their derived stromal cells, osteoblasts and bone marrow adipocytes (BMAs) provide the niche microenvironment to support the self-renewal and differentiation of hematopoietic stem cells (HSCs). However, it’s still largely mysterious how the bone-fat balance is disrupted and whether marrow adiposity contributes to the skewed differentiation of HSCs toward myeloid over lymphoid cells. Here we showed that the O-linked β-N-acetylglucosamine (O-GlcNAc) modification on intracellular proteins determined the adipogenic vs. osteogenic differentiation of SSCs. Conditional deletion of O-GlcNAc transferase (OGT) in Osx1+ cells promoted BMA formation while impaired osteoblast development and bone ossification, which resulted in defective B cell development. To determine the role of BM adipokines in hematopoiesis, we selectively ablated Kit ligand (Kitl) in Osx1+ and Adipoq+ lineages. Both Osx1-Kitl KO and Adipoq-Kitl KO mice lost myeloid progenitors in BM and developed macrocytic anemia. Collectively, our data identified protein O-GlcNAcylation as a novel regulator of SSCs differentiation and demonstrated that BMAs are functionally essential for unperturbed hematopoiesis.