Role of DMP1 Mediated Paracrine Signaling in Vasculogenesis

对于牙本质修复或再生，及时出现血管是很重要的。 因此，再生牙本质-牙髓复合体的组织工程策略需要 建立输送氧气、营养物质、激素、免疫细胞、矿物质的血管系统 还有助于在炎症过程中清除细胞碎片和代谢废物 和愈合的再生阶段。牙本质基质蛋白1(DMP1)是牙本质细胞中的一种关键调节蛋白。 骨和牙本质矿化。我们首先证明了它在 羟基磷灰石在骨和骨细胞外基质中的形核和生长调控 牙本质。随后，我们证明了DMP1定位于 前成骨细胞和前成牙本质细胞，从而作为信号分子促进 这些前体细胞的分化。最近我们发现DMP1可以刺激血管紧张素转换酶 成骨前细胞和成牙本质前细胞内钙的释放。细胞内耗竭 内质网中的钙离子导致内质网应激。细胞通过以下途径应对内质网应激 激活“未折叠蛋白反应”(UPR)。我们最近的观察之一是DMP1 刺激可促进血管内皮生长因子等促血管生成因子的分泌。因此，我们 DMP1激活的内质网应激促进成人转化的假说 干细胞如牙髓干细胞向内皮细胞转化从而促进 血管生成。为了确定DMP1促进的机制 血管生成，我们将研究UPR信号通路。普遍定期审议由三个ER发起 跨膜蛋白，其中我们的初步数据显示，DMP1刺激激活 UPR的ATF6(激活转录因子6)臂。因此，我们在此建议 内质网环境下ATF6介导血管内皮生长因子转录调控机制的研究 压力。在牙本质修复和再生过程中，一个主要的挑战是细胞的维护 生存能力取决于有功能的血管系统的可用性。因此，我们将 在活体牙髓中测试DMP1的体内血管生成能力和治疗潜力 再生模型。 了解DMP1的复杂功能可能对开发治疗方法有价值 骨或牙齿的骨折修复以恢复丢失、损坏或病变的牙本质髓 很复杂。

For dentin repair or regeneration, it is important to have the timely appearance of blood vessels. Therefore, tissue-engineering strategies to regenerate the dentin-pulp complex require establishment of vasculature to deliver oxygen, nutrients, hormones, immune cells, minerals and also help in clearing cellular debris and metabolic waste products during the inflammatory and regenerative phases of healing. DMP1 (dentin matrix protein1) is a key regulatory protein in bone and dentin mineralization. We first demonstrated that it has a regulatory role in the regulation of hydroxyapatite nucleation and growth in the extracellular matrices of bone and dentin. Subsequently, we demonstrated that DMP1 was localized in the nucleus of preosteoblasts and preodontoblasts and thus served as a signaling molecule and promoted the differentiation of these precursor cells. Recently we discovered that DMP1 can stimulate the release of intracellular calcium in preosteoblasts and preodontoblasts. Depletion of intracellular calcium from the endoplasmic reticulum leads to ER stress. Cells cope with ER stress by activating the “Unfolded protein response” (UPR). One of our recent observations is that DMP1 stimulation can promote the secretion of VEGF and other pro-angiogenic factors. Therefore, we hypothesize that ER stress activated by DMP1 functions to promote the transformation of adult stem cells such as dental pulp stem cells to endothelial cells and thereby promote vasculogenesis. In order to determine the mechanism by which DMP1 promotes vasculogenesis, we will examine the UPR signaling pathway. The UPR is initiated by three ER transmembrane proteins, of which our preliminary data show that DMP1 stimulation activated the ATF6 (Activating Transcription Factor 6) arm of the UPR. Accordingly, here we propose to study the mechanism by which ATF6 mediate transcriptional regulation of VEGF under ER stress. During dentin repair and regeneration, a major challenge is the maintenance of cell viability which depends on the availability of a functional vascular system. Accordingly, we will test the in-vivo vasculogenic competence and therapeutic potential of DMP1 in an in vivo pulp regeneration model. Understanding the complex functions of DMP1 could be valuable to develop therapies for fracture repair in bone or in the tooth to restore lost, damaged or diseased dentin-pulp complex.