Periodontal bone defects, primarily caused by periodontitis, are highly prevalent in clinical settings and manifest as bone fenestration, dehiscence, or attachment loss, presenting a significant challenge to oral health. In regenerative medicine, harnessing developmental principles for tissue repair offers promising therapeutic potential. Of particular interest is the condensation of progenitor cells, an essential event in organogenesis that has inspired clinically effective cell aggregation approaches in dental regeneration. However, the precise cellular coordination mechanisms during condensation and regeneration remain elusive. Here, taking the tooth as a model organ, we employed single-cell RNA sequencing to dissect the cellular composition and heterogeneity of human dental follicle and dental papilla, revealing a distinct Platelet-derived growth factor receptor alpha (PDGFRA) mesenchymal stem/stromal cell (MSC) population with remarkable odontogenic potential. Interestingly, a reciprocal paracrine interaction between PDGFRA⁺ dental follicle stem cells (DFSCs) and CD31⁺ Endomucin⁺ endothelial cells (ECs) was mediated by Vascular endothelial growth factor A (VEGFA) and Platelet-derived growth factor subunit BB (PDGFBB). This crosstalk not only maintains the functionality of PDGFRA⁺ DFSCs but also drives specialized angiogenesis. In vivo periodontal bone regeneration experiments further reveal that communication between PDGFRA⁺ DFSC aggregates and recipient ECs is essential for effective angiogenic-osteogenic coupling and rapid tissue repair. Collectively, our results unravel the importance of MSC-EC crosstalk mediated by the VEGFA and PDGFBB-PDGFRA reciprocal signaling in orchestrating angiogenesis and osteogenesis. These findings not only establish a framework for deciphering and promoting periodontal bone regeneration in potential clinical applications but also offer insights for future therapeutic strategies in dental or broader regenerative medicine.
Receptor, Platelet-Derived Growth Factor alpha/metabolism* ; Humans ; Neovascularization, Physiologic/physiology* ; Dental Sac/cytology* ; Single-Cell Analysis ; Transcriptome ; Mesenchymal Stem Cells/metabolism* ; Bone Regeneration ; Animals ; Dental Papilla/cytology* ; Periodontium/physiology* ; Stem Cells/metabolism* ; Regeneration ; Angiogenesis

Objective:To analyze the immune microenvironment characteristics of human dental follicle tissues from the third molars and to explore the mutual communication and the effects of innate immune cells and adaptive immune cells within the dental follicle.Methods:Sequencing data(GSA-Human:HRA008022)in the GSA database were analyzed.Bioinformatics tools were employed for gene identification and GO enrichment analysis was performed to define the biological function of innate and adaptive immune cells.CellChat analysis was used for explaining intercellular communication among immune cell populations.Results:Using t-SNE dimen-sionality reduction analysis for immune cell populations,innate immune cell populations were obtained,including innate lymphoid cells,dendritic cells,mast cells and macrophages,and adaptive immune cell populations including T cells and B cells.Pearson corre-lation analysis showed that innate immune cells,specifically innate lymphoid cells and macrophages,had a strong correlation with adap-tive immune cell populations.GO enrichment analysis revealed mutual coordination among innate immune cell populations and regulato-ry effects on adaptive immune cell populations.Further CellChat analysis indicated biological signal transmission between innate and a-daptive immune cell populations,with CLEC,MIF,ADGRE5,COLLAGEN and MIF signaling pathways is the most significant.Con-clusion:Dental follicle tissues are rich in immune cells and innate immune cell populations interact with adaptive immune cells to regulate immune responses and participate in maintaining the homeostasis of dental follicle.