O-GlcNAc glycosylation orchestrates fate decision and niche function of bone marrow stromal progenitors
- University of Minnesota, United States
- Nanjing Agricultural University, China
- Western University of Health Sciences, United States
- The Ohio State University, United States
- University of South Carolina, United States
- University of California, San Francisco, United States
- Mayo Clinic, United States
Abstract
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.
Data availability
All data generated or analyzed during this study are included in the manuscript and supporting file. Supplemental tables have been provided for Mass spectrometry, primer sequences, and antibody list.
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Author details
Funding
National Natural Science Foundation of China (32170847)
- Zan Huang
National Institutes of Health (R01 AI162678)
- Hu Zeng
National Institutes of Health (R01 AI139420)
- Hai-Bin Ruan
National Institutes of Health (R01 AI162791)
- Hai-Bin Ruan
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal experiments were approved by the institutional animal care and use committee of the University of Minnesota (protocol # 2112-39682A).
Copyright
© 2023, Zhang et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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O-GlcNAc glycosylation orchestrates fate decision and niche function of bone marrow stromal progenitors
eLife 12:e85464.
https://doi.org/10.7554/eLife.85464
