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纤维生素的突变在骨发育不良的骨发育不良中失调

Neha E H Dinesh¹, Justine Rousseau², Deane F Mosher³

¹Faculty of Medicine and Health Sciences, Department of Anatomy and Cell Biology, McGill University, 3640 University Street, Montreal, QC, Canada.

Cellular and molecular life sciences : CMLS

|October 5, 2024

概括

纤维肌菌素突变破坏蛋白质分泌,导致细胞应激,并在脊髓介质细胞形症中导致软骨发育受损. 补充纤维素或TGFβ1可以挽救这些缺陷.

科学领域:

生物化学生物化学
细胞生物学细胞生物学
遗传学遗传学是一个

背景情况:

纤维蛋白 (FN) 对于脊椎动物器官发育至关重要.
在FN中发生的突变会导致脊髓甲基细胞不形成症 (SMDCF),这是一种骨疾病.
与FN相关的骨发育不良的细胞机制尚未完全理解.

研究的目的:

调查FN突变对中细胞干细胞 (MSCs) 和SMDCF中体发生的影响.
阐明SMDCF骨发育缺陷背后的分子途径.

主要方法:

产生患者衍生诱导多能干细胞 (iPSCs) 作为SMDCF模型.
分析了MSC中的蛋白质分泌,细胞内/细胞外FN水平和细胞应激标志物.
进行了大量的RNA测序,并评估了MSC分化成冠状细胞的情况.
研究了外源性FN和TGFβ1补充的作用.

主要成果:

FN突变损害了蛋白质分泌,增加了细胞内FN,减少了细胞外FN.
在细胞质囊泡中FN和ER伴侣的积累导致了细胞应激和线粒体功能障碍.
突变的MSCs表现为受损的冠状体生成,降低了TGFβ1表达和受损的增殖.
外源性FN或TGFβ1补充可以挽救原生缺陷.

结论:

在MSC中,FN突变会破坏蛋白质稳态和细胞功能.
改变的软体生成和降低的TGFβ1是FN相关的骨发育不良的关键机制.
针对FN和TGFβ1通路为SMDCF提供了潜在的治疗策略.

关键词:

混凝土生成 (chondrogenesis) 是一种不同化的差异化纤维纤维素的生长方式诱导的多能干细胞干细胞骨发育不良症骨发育不良症

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