Harvard School of Dental Medicine, Research and Education Building, Boston, MA, USA.
J Dent Res. 2022 Aug;101(9):1119-1126. doi: 10.1177/00220345221086858. Epub 2022 Apr 11.
Dental pain is a persistent, detrimental public health issue that requires a better understanding of the mechanisms of tooth pain and inflammation in order to develop more effective treatments. Calcitonin gene-related peptide (CGRP) and dental pulp cells are promising candidates for mediating tooth pain and generating reparative dental tissues, respectively, but their behavior in the context of pulpitis remains elusive. The mouse incisor requires Sonic hedgehog (Shh) secreted from sensory nerves to continuously regenerate. However, it is unknown whether sensory nerves also regulate the comparatively nonregenerative mouse molar through CGRP and Shh. This is an important knowledge gap to fill since mouse incisors differ biologically from human teeth, while mouse and human molars are similar. In this work, we identified that molar pulp cells express CGRP receptor and Gli1, a Hedgehog (Hh) signaling protein found to label a dental stem cell population in the mouse incisor. We also observed in a mouse molar injury model that Hh signaling was activated and Shh expression was upregulated in vivo. We then determined in vitro that Shh and CGRP regulate differentiation of primary mouse molar and incisor pulp cells and a human dental pulp stem cell line. Furthermore, conditioned media from stimulated sensory neurons induced Hh signaling activation and inflammatory gene expression in primary molar pulp cells, which was abolished by inhibition of either Shh or CGRP. Our results suggest that CGRP and Shh signaling may promote an inflammatory response after injury in the molar and that activated sensory nerves secrete CGRP and Shh to regulate molar pulp cell expansion and differentiation into odontoblast-like cells for dentin repair. Thus, CGRP/Shh signaling should be considered for new strategies that seek to manage pain or dentin regeneration in the molar.
牙齿疼痛是一种持续存在的、有害的公共健康问题，需要更好地了解牙齿疼痛和炎症的机制，以便开发更有效的治疗方法。降钙素基因相关肽 (CGRP) 和牙髓细胞分别是介导牙齿疼痛和产生修复性牙组织的有前途的候选物，但它们在牙髓炎背景下的行为仍难以捉摸。小鼠切牙需要感觉神经分泌的 Sonic hedgehog (Shh) 来持续再生。然而，目前尚不清楚感觉神经是否也通过 CGRP 和 Shh 来调节相对不可再生的小鼠磨牙。这是一个需要填补的重要知识空白，因为小鼠切牙在生物学上与人类牙齿不同，而小鼠和人类磨牙相似。在这项工作中，我们鉴定出磨牙牙髓细胞表达 CGRP 受体和 Gli1，这是 Hedgehog (Hh) 信号蛋白，在小鼠切牙中被发现标记一个牙源性干细胞群体。我们还在小鼠磨牙损伤模型中观察到，Hh 信号在体内被激活，Shh 表达上调。然后，我们在体外确定 Shh 和 CGRP 调节原代小鼠磨牙和切牙牙髓细胞以及人牙髓干细胞系的分化。此外，刺激感觉神经元的条件培养基诱导原代磨牙牙髓细胞中 Hh 信号的激活和炎症基因的表达，该表达被 Shh 或 CGRP 的抑制所消除。我们的研究结果表明，CGRP 和 Shh 信号可能在磨牙损伤后促进炎症反应，而激活的感觉神经分泌 CGRP 和 Shh 来调节磨牙牙髓细胞的扩张和分化为成牙本质样细胞，以修复牙本质。因此，CGRP/Shh 信号应该被考虑用于新的策略，以寻求管理磨牙中的疼痛或牙本质再生。
