Bone-derived mesenchymal stem cells (MSCs) reside in a hypoxic niche that maintains their differentiation potential. While hypoxia (low oxygen concentration) was reported to critically support stem cell function and osteogenesis, the molecular events triggering changes in stem cell fate decisions in response to normoxia (high oxygen concentration) remain elusive. Here, we study the impact of normoxia on mitochondrial–nuclear communication during stem cell differentiation. We show that normoxia-cultured murine MSCs undergo profound transcriptional alterations which cause irreversible osteogenesis defects. Mechanistically, high oxygen promotes chromatin compaction and histone hypo-acetylation, particularly on promoters and enhancers of osteogenic genes. Although normoxia induces metabolic rewiring resulting in elevated acetyl-CoA levels, histone hypo-acetylation occurs due to the trapping of acetyl-CoA inside mitochondria owing to decreased citrate carrier (CiC) activity. Restoring the cytosolic acetyl-CoA pool remodels the chromatin landscape and rescues the osteogenic defects. Collectively, our results demonstrate that the metabolism–chromatin–osteogenesis axis is perturbed upon exposure to high oxygen levels and identifies CiC as a novel, oxygen-sensitive regulator of the MSC function.

中文翻译：

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缺氧通过促进乙酰辅酶A介导的线粒体-核通讯来促进成骨


骨源性间充质干细胞 (MSC) 存在于低氧环境中，可维持其分化潜力。虽然据报道缺氧（低氧浓度）对干细胞功能和骨生成至关重要，但响应常氧（高氧浓度）而触发干细胞命运决定变化的分子事件仍然难以捉摸。在这里，我们研究常氧对干细胞分化过程中线粒体-核通讯的影响。我们发现，常氧培养的小鼠间充质干细胞经历了深刻的转录改变，导致不可逆的成骨缺陷。从机制上讲，高氧促进染色质压缩和组蛋白低乙酰化，特别是在成骨基因的启动子和增强子上。尽管含氧量正常会诱导代谢重连，导致乙酰辅酶 A 水平升高，但由于柠檬酸载体 (CiC) 活性降低，乙酰辅酶 A 被捕获在线粒体内，因此会发生组蛋白低乙酰化。恢复细胞质乙酰辅酶A池可以重塑染色质景观并挽救成骨缺陷。总的来说，我们的结果表明，代谢-染色质-成骨轴在暴露于高氧水平时受到干扰，并将 CiC 确定为 MSC 功能的新型氧敏感调节剂。