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缺氧/HIF信号负面调节辐射暴露后的骨髓脂肪

Cheyenne A Jones, Wendi Guo, Kiana A Gunn

bioRxiv : the preprint server for biology

|September 18, 2025

概括

放射治疗可以通过增加骨髓脂肪组织 (MAT) 来损害骨. 我们的研究发现,阻断某些骨细胞中缺氧诱导因子 (HIF) 信号传递,意外地加剧了这种辐射诱导的脂肪积累,揭示了新的细胞机制.

科学领域:

骨生物学和辐射瘤学
骨微环境 (BME) 调节的细胞和分子机制.

背景情况:

放射治疗虽然对癌症治疗至关重要,但会对正常组织,特别是骨造成重大损伤.
辐射诱导的骨毒性包括造血功能障碍,骨体积减少和骨髓脂肪组织 (MAT) 增加,导致骨折风险更高.
骨髓微环境 (BME) 通常是缺氧的,激活缺氧诱导因子 (HIF) 信号,这在细胞对压力的反应中起作用.

研究的目的:

调查缺氧/HIF信号在辐射诱导的骨髓脂肪组织 (MAT) 扩张中的作用.
为了确定特定的细胞群和信号通路,参与调节辐射暴露后的MAT.

主要方法:

生成并分析条件淘汰赛小鼠 (aP2Cre;Hif-1fl/fl;Hif-2fl/fl) 来评估辐射后aP2表达细胞中的HIF信号.
使用aP2CreRosa26tdTomato/+小鼠的谱系追踪来追踪aP2表达细胞的分化.
研究了HIFα转录因子除在LepRCre表达骨干细胞对辐射诱导的MAT扩张的影响.

主要成果:

辐射暴露导致了快速和持续的MAT积累,脂肪细胞局部化到缺氧区域.
与对照组相比,aP2表达细胞中HIF信号的条件删除意外地加剧了辐射诱导的MAT扩张.
谱系追踪表明,aP2-表达细胞并不是主要分化为脂肪细胞,巨细胞或内皮细胞,而是通过非特征化的树突群体影响MAT形成.
在LepRCre表达骨干细胞中切除HIFα并没有影响辐射诱导的MAT扩张.

结论:

结果揭示了以前未知的脂肪细胞调节细胞群,其中依赖HIF的活动通常限制了压力诱导的骨髓脂肪.
这项研究为辐射如何破坏骨髓微环境并促进MAT扩张提供了新的机制性见解.
这些结果有助于进一步了解辐射诱导骨脆弱性的细胞和分子驱动因素,并确定潜在的治疗点.

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