The function of Hedgehog signaling in maintaining the dental mesenchymal stem cells

摘要 牙齿间充质干细胞是一组重要的细胞，对牙齿发育至关重要， 稳态和对损伤修复的反应。最近的研究表明，在小鼠切牙中，Gli 1- LacZ阳性细胞为牙本质形成提供源源不断的成牙本质细胞。但具体 Hedgehog信号在调节牙间充质干细胞中的功能仍然是难以捉摸的。EVC 综合征是一种常染色体隐性软骨发育不良。我们小组和其他人的研究表明 EvC综合征的致病基因Evc和Evc 2是Hedgehog信号传导的正调控因子。我们 最近的研究还表明，Evc 2在牙间充质中的功能丧失导致了延迟的 成牙本质细胞分化在这里提出的工作中，我们将使用Evc 2突变小鼠作为模型， 研究Hedgehog信号通路在牙源性间充质干细胞调控中的作用。鉴于 根据初步的数据和最近的研究，我们假设Hedgehog信号促进了细胞的分化， 神经胶质祖细胞转化为成牙本质祖细胞，以及由于 evc 2功能丧失导致成牙本质细胞分化延迟。我们的假设将由 以下两个目的：1）证明牙齿间充质中的Hedgehog信号传导对于 发育过程中成牙本质细胞祖细胞的数量和能力; 2）证明Hedgehog信号传导 在胶质祖细胞中的表达对于随后向成牙本质细胞祖细胞的分化至关重要。成果 的拟议工作将揭示导致埃利斯牙齿异常的病理生理机制- 货车Creveld（EvC）综合征，并为支持未来的牙齿再生研究提供知识。

Abstract Dental mesenchymal stem cells are an important group of cells, which are critical for tooth development, homeostasis and response to injury repairs. Recent studies have demonstrated that in the mouse incisor, Gli1- LacZ positive cells contribute to continuously supplying odontoblasts for dentin formation. However, the exact function of Hedgehog signaling in regulating the dental mesenchymal stem cells remained to be elusive. EvC syndrome is an autosomal recessive chondrodysplasia. Studies form our group and others have demonstrated that the causative genes for EvC syndrome, Evc and Evc2, are positive regulators of Hedgehog signaling. Our recent work also demonstrates that Evc2 loss of function in the dental mesenchyme leads to delayed odontoblast differentiation. In the proposed works here, we will use Evc2 mutant mice as models to characterize the function of Hedgehog signaling in regulating the dental mesenchymal stem cells. Given the preliminary data and the recent studies, we hypothesize that Hedgehog signaling promote differentiation of glial progenitor cells to odontoblast progenitor cells and that incompetent odontoblast progenitor cells due to Evc2 loss of function leads to delayed odontoblast differentiation. Our hypothesis will be examined by the following two aims: 1) Demonstrate that Hedgehog signaling in the dental mesenchyme is important for odontoblast progenitor cell number and competence during development; 2) Demonstrate Hedgehog signaling in the glial progenitor cells is critical for subsequent differentiation to odontoblast progenitor cells. The outcome of the proposed work will uncover the patho-physiological mechanism leading to tooth abnormalities in Ellis- van Creveld (EvC) syndrome and provide knowledge for supporting future tooth regeneration studies.