O-GlcNAc glycosylation orchestrates fate decision and niche function of bone marrow stromal progenitors.
O-GlcNAc glycosylation orchestrates fate decision and niche function of bone marrow stromal progenitors.
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DOI：
10.7554/elife.85464
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发表时间：
2023-03-02
期刊：
影响因子：
7.7
通讯作者：
Ruan HB
中科院分区：
文献类型：
--
作者：
Zhang Z;Huang Z;Awad M;Elsalanty M;Cray J;Ball LE;Maynard JC;Burlingame AL;Zeng H;Mansky KC;Ruan HB
在哺乳动物中，骨髓（BM）基质和造血祖细胞之间的相互作用有助于骨-BM稳态。围产期骨生长和骨化提供了一个微环境的过渡到明确的造血;然而，机制和相互作用协调骨骼和造血系统的发展仍然在很大程度上是未知的。在这里，我们建立了细胞内O-连接的β-N-乙酰葡萄糖胺（O-GlcNAc）修饰作为翻译后开关，决定了早期骨髓基质细胞（BMSCs）的分化命运和生态位功能。通过修饰和激活RUNX 2，O-GlcNAc化促进BMSC的成骨分化和基质IL-7表达以支持淋巴细胞生成。相反，C/EBPβ依赖的骨髓脂肪生成和骨髓造血干细胞因子（SCF）的表达被O-GlcNAc化抑制。在小鼠中，BMSC中的O-GlcNAc转移酶（OGT）的降解导致骨形成受损、骨髓肥胖增加以及B细胞淋巴细胞生成缺陷和骨髓过度生成。因此，BMSC的成骨和成脂分化的平衡由转录因子的相互O-GlcNAc调节决定，其同时形成造血生态位。
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.