Role of DMP1 Mediated Paracrine Signaling in Vasculogenesis

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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.