Atp6i缺陷小鼠模型揭示转化生长因子-β1 /Smad2/3是调节成牙细胞分化和牙根形成的关键信号通路。

IF 10.8 1区 医学 Q1 DENTISTRY, ORAL SURGERY & MEDICINE International Journal of Oral Science Pub Date : 2023-08-21 DOI:10.1038/s41368-023-00235-2
Jue Wang, Abigail McVicar, Yilin Chen, Hong-Wen Deng, Zhihe Zhao, Wei Chen, Yi-Ping Li
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引用次数: 0

摘要

调控牙根发育和成牙细胞分化的生物分子机制尚不清楚。我们发现,Atp6i缺陷小鼠(Atp6i-/-)阻止了牙根的形成,这表明Hertwig's上皮根鞘(HERS)的进展被截断。此外,Atp6i缺乏显著降低了负责根形成的根状牙原细胞的增殖和分化。Atp6i-/-小鼠牙槽骨中成牙细胞分化标记基因(Col1a1、Nfic、Dspp和Osx)的表达显著降低。Atp6i-/-小鼠样本RNA-seq分析结果显示成牙细胞标记物表达水平下降。此外,Smad2/3激活显著降低,抑制Atp6i-/-成牙细胞中转化生长因子-β (TGF-β)信号传导。通过用Atp6i-/-或野生型OC骨吸收条件培养基处理牙髓前体细胞,我们发现后者能促进成牙髓细胞分化,表现为成牙髓细胞分化标记基因(Nfic、Dspp、Osx和Runx2)表达增加。这种增加的表达被抗tgf -β1抗体中和显著阻断,而Atp6i-/- OC条件培养基显著减弱成牙细胞分化和Smad2/3的激活。重要的是,异位TGF-β1部分挽救了Atp6i-/-小鼠牙胚在小鼠肾胶囊下移植的根发育和根本质沉积。总之,我们的新数据表明,OC功能障碍阻止了TGF-β1从牙槽骨基质中释放,可能会通过受损的根状成牙细胞分化导致骨质疏松相关的根形成。因此,本研究发现TGF-β1 /Smad2/3是调节成牙细胞分化和牙根形成的关键信号通路,可能有助于未来牙根再生的治疗方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Atp6i deficient mouse model uncovers transforming growth factor-β1 /Smad2/3 as a key signaling pathway regulating odontoblast differentiation and tooth root formation.

The biomolecular mechanisms that regulate tooth root development and odontoblast differentiation are poorly understood. We found that Atp6i deficient mice (Atp6i-/-) arrested tooth root formation, indicated by truncated Hertwig's epithelial root sheath (HERS) progression. Furthermore, Atp6i deficiency significantly reduced the proliferation and differentiation of radicular odontogenic cells responsible for root formation. Atp6i-/- mice had largely decreased expression of odontoblast differentiation marker gene expression profiles (Col1a1, Nfic, Dspp, and Osx) in the alveolar bone. Atp6i-/- mice sample RNA-seq analysis results showed decreased expression levels of odontoblast markers. Additionally, there was a significant reduction in Smad2/3 activation, inhibiting transforming growth factor-β (TGF-β) signaling in Atp6i-/- odontoblasts. Through treating pulp precursor cells with Atp6i-/- or wild-type OC bone resorption-conditioned medium, we found the latter medium to promote odontoblast differentiation, as shown by increased odontoblast differentiation marker genes expression (Nfic, Dspp, Osx, and Runx2). This increased expression was significantly blocked by anti-TGF-β1 antibody neutralization, whereas odontoblast differentiation and Smad2/3 activation were significantly attenuated by Atp6i-/- OC conditioned medium. Importantly, ectopic TGF-β1 partially rescued root development and root dentin deposition of Atp6i-/- mice tooth germs were transplanted under mouse kidney capsules. Collectively, our novel data shows that the prevention of TGF-β1 release from the alveolar bone matrix due to OC dysfunction may lead to osteopetrosis-associated root formation via impaired radicular odontoblast differentiation. As such, this study uncovers TGF-β1 /Smad2/3 as a key signaling pathway regulating odontoblast differentiation and tooth root formation and may contribute to future therapeutic approaches to tooth root regeneration.

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来源期刊
International Journal of Oral Science
International Journal of Oral Science DENTISTRY, ORAL SURGERY & MEDICINE-
CiteScore
31.80
自引率
1.30%
发文量
53
审稿时长
>12 weeks
期刊介绍: The International Journal of Oral Science covers various aspects of oral science and interdisciplinary fields, encompassing basic, applied, and clinical research. Topics include, but are not limited to: Oral microbiology Oral and maxillofacial oncology Cariology Oral inflammation and infection Dental stem cells and regenerative medicine Craniofacial surgery Dental material Oral biomechanics Oral, dental, and maxillofacial genetic and developmental diseases Craniofacial bone research Craniofacial-related biomaterials Temporomandibular joint disorder and osteoarthritis The journal publishes peer-reviewed Articles presenting new research results and Review Articles offering concise summaries of specific areas in oral science.
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