CGRP-mediated neuro-vascular-pulp cell crosstalk is essential for dental pulp repair

Introduction: The repair of dental pulp injury is the cornerstone of vital pulp therapy. Traditional research has predominantly focused on the roles of immune cells, vascular endothelial cells, and dental pulp stem cells, often overlooking the active regulatory functions of the sensory neural network. Sensory nerve fibers constitute nearly 40% of the dental pulp volume, and their released neuropeptides, such as calcitonin Gene-Related Peptide (CGRP), are hypothesized to coordinate the repair process via intercellular communication. This study aims to systematically elucidate the molecular mechanisms by which sensory nerves and their key neuropeptide, CGRP, regulate angiogenesis and the activation of stromal cells within the injured pulp microenvironment, thereby providing a theoretical basis for novel pulp regeneration strategies targeting neural signaling pathways. Methods: The cell-cell communication network in dental pulp was using single-cell transcriptome analysis (GSE197289, GSE274562, GSE280528). A series of in vitrocellular experiments, including qPCR, Western blot, immunofluorescence, scratch wound healing assay, and tube formation assay, were employed to evaluate the effects of CGRP on cell migration, angiogenesis, and mineralization. A mouse model of dentin-pulp injury was established, and the in vivoangiogenic changes were validated through intervention with the CGRP receptor antagonist BIBN4096BS. RNA sequencing was conducted to analyze the transcriptional reprogramming of human dental pulp cells (DPCs) induced by CGRP. Results: signals) in the injured pulp area of mice. Conclusion: This study elucidates that the sensory neuropeptide CGRP drives a "neuro-vascular-stromal cell" collaborative network during pulp repair through dual pathways: directly activating endothelial cell function and indirectly modulating the paracrine profile of dental pulp cells (e.g., upregulating VEGFA), thereby promoting angiogenesis and stem cell differentiation. This discovery not only deepens the understanding of the self-repair mechanisms of dental pulp but also offers a new perspective for developing precise vital pulp therapy strategies targeting CGRP signaling, such as modulating the neuro-microenvironment interaction.