骨骼干细胞中Notch信号的缺失会随着衰老而增强骨形成。

IF 14.3 1区 医学 Q1 CELL & TISSUE ENGINEERING
Lindsey H Remark, Kevin Leclerc, Malissa Ramsukh, Ziyan Lin, Sooyeon Lee, Backialakshmi Dharmalingam, Lauren Gillinov, Vasudev V Nayak, Paulo El Parente, Margaux Sambon, Pablo J Atria, Mohamed A E Ali, Lukasz Witek, Alesha B Castillo, Christopher Y Park, Ralf H Adams, Aristotelis Tsirigos, Sophie M Morgani, Philipp Leucht
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引用次数: 0

摘要

骨骼干细胞和祖细胞(SSPCs)进行骨骼维护和修复。随着年龄的增长,它们产生的成骨细胞越来越少,脂肪细胞越来越多,导致骨骼完整性的丧失。这种有害转化的分子机制在很大程度上是未知的。单细胞RNA测序显示,在衰老过程中,SSPCs中的Notch信号传导升高。为了检测Notch活性增加的作用,我们在体内SSPCs中删除了Nicastrin,一种重要的Notch通路成分。中年条件敲除小鼠表现出SSPC骨谱系基因表达升高、骨小梁质量增加、骨髓肥胖减少和骨修复增强。因此,Notch调节SSPC细胞的命运决定,调节Notch信号可改善骨骼衰老表型,增加骨量,甚至超过年轻小鼠。最后,我们确定转录因子Ebf3是SSPCs中Notch信号传导的下游介体,它随着衰老而失调,强调它是一个很有前途的治疗靶点,可以使衰老的骨骼恢复活力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Loss of Notch signaling in skeletal stem cells enhances bone formation with aging.

Loss of Notch signaling in skeletal stem cells enhances bone formation with aging.

Loss of Notch signaling in skeletal stem cells enhances bone formation with aging.

Loss of Notch signaling in skeletal stem cells enhances bone formation with aging.

Skeletal stem and progenitor cells (SSPCs) perform bone maintenance and repair. With age, they produce fewer osteoblasts and more adipocytes leading to a loss of skeletal integrity. The molecular mechanisms that underlie this detrimental transformation are largely unknown. Single-cell RNA sequencing revealed that Notch signaling becomes elevated in SSPCs during aging. To examine the role of increased Notch activity, we deleted Nicastrin, an essential Notch pathway component, in SSPCs in vivo. Middle-aged conditional knockout mice displayed elevated SSPC osteo-lineage gene expression, increased trabecular bone mass, reduced bone marrow adiposity, and enhanced bone repair. Thus, Notch regulates SSPC cell fate decisions, and moderating Notch signaling ameliorates the skeletal aging phenotype, increasing bone mass even beyond that of young mice. Finally, we identified the transcription factor Ebf3 as a downstream mediator of Notch signaling in SSPCs that is dysregulated with aging, highlighting it as a promising therapeutic target to rejuvenate the aged skeleton.

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来源期刊
Bone Research
Bone Research CELL & TISSUE ENGINEERING-
CiteScore
20.00
自引率
4.70%
发文量
289
审稿时长
20 weeks
期刊介绍: Established in 2013, Bone Research is a newly-founded English-language periodical that centers on the basic and clinical facets of bone biology, pathophysiology, and regeneration. It is dedicated to championing key findings emerging from both basic investigations and clinical research concerning bone-related topics. The journal's objective is to globally disseminate research in bone-related physiology, pathology, diseases, and treatment, contributing to the advancement of knowledge in this field.
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