O-GlcNAc glycosylation orchestrates fate decision and niche function of bone marrow stromal progenitors
Zengdi Zhang,
Zan Huang,
Mohamed Awad,
Mohammed Elsalanty,
James Cray,
Lauren E Ball,
Jason C Maynard,
Alma L Burlingame,
Hu Zeng,
Kim C Mansky,
Hai-Bin Ruan
Affiliations
Zengdi Zhang
Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, United States
Zan Huang
Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, United States; Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China; National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural University, Nanjing, China
Mohamed Awad
Department of Medical Anatomical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, United States
Mohammed Elsalanty
Department of Medical Anatomical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, United States
James Cray
Department of Biomedical Education and Anatomy, The Ohio State University College of Medicine, and Division of Biosciences, The Ohio State University College of Dentistry, Columbus, United States
Lauren E Ball
Department of Cell and Molecular Pharmacology & Experimental Therapeutics, Medical University of South Carolina, Charleston, United States
Jason C Maynard
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States
Alma L Burlingame
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States
Hu Zeng
Division of Rheumatology, Department of Internal Medicine, Mayo Clinic, Rochester, United States; Department of Immunology, Mayo Clinic, Rochester, United States
Kim C Mansky
Department of Developmental and Surgical Sciences, School of Dentistry, University of Minnesota, Minneapolis, United States
Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, United States; Center for Immunology, University of Minnesota Medical School, Minneapolis, United States
In mammals, interactions between the bone marrow (BM) stroma and hematopoietic progenitors contribute to bone-BM homeostasis. Perinatal bone growth and ossification provide a microenvironment for the transition to definitive hematopoiesis; however, mechanisms and interactions orchestrating the development of skeletal and hematopoietic systems remain largely unknown. Here, we establish intracellular O-linked β-N-acetylglucosamine (O-GlcNAc) modification as a posttranslational switch that dictates the differentiation fate and niche function of early BM stromal cells (BMSCs). By modifying and activating RUNX2, O-GlcNAcylation promotes osteogenic differentiation of BMSCs and stromal IL-7 expression to support lymphopoiesis. In contrast, C/EBPβ-dependent marrow adipogenesis and expression of myelopoietic stem cell factor (SCF) is inhibited by O-GlcNAcylation. Ablating O-GlcNAc transferase (OGT) in BMSCs leads to impaired bone formation, increased marrow adiposity, as well as defective B-cell lymphopoiesis and myeloid overproduction in mice. Thus, the balance of osteogenic and adipogenic differentiation of BMSCs is determined by reciprocal O-GlcNAc regulation of transcription factors, which simultaneously shapes the hematopoietic niche.
