Chemotactic Signalling Triggers Dental Pulp Fibrosis in the Stem Cell Niches During
Aging often triggers dental pulp fibrosis, leading to various clinical repercussions, including heightened vulnerability to dental infections, compromised tooth vitality, and reduced responsiveness to dental interventions. Despite its common occurrence in clinical settings, the precise molecular mechanisms driving this condition remain elusive. Leveraging single-cell transcriptome analysis from both our own and publicly available datasets, we identified Ccrl2+ macrophages as particularly prone to susceptibility during the early stages of aging. Notably, dental pulp progenitors exhibiting high expression of Rarres2, a unique ligand for Ccrl2, orchestrate the selective recruitment of a specific macrophage population to the stem cell niches. Subsequently, this results in the presentation of the ligand-receptor complex to Cmklr1, a receptor ubiquitously expressed among all macrophage populations, ultimately leading to macrophage activation and expansion via the Rarres2/Ccrl2/Cmklr1 axis. Our study, supported by rigorous experimental validation, conclusively shows that macrophage activation and expansion in stem cell niches lead to increased secretion of proinflammatory factors, which contribute to dental pulp fibrosis during aging. Our data reveals the complex molecular dynamics of dental pulp aging, particularly focusing on interactions within the immune microenvironment. It offers a novel perspective on potential treatments for age-related pulp diseases, highlighting the role of macrophages and the possibility of modifying the immune microenvironment for therapeutic benefit. Overall design: Mouse incisors from mandibles were carefully dissected from 15 C57BL/6 mice aged 8-12 months. The incisor pulp, with minimal inclusion of dental epithelium, was isolated and analysed using scRNAseq.