Single-cell transcriptomics identifies PDGFRA⁺ progenitors orchestrating angiogenesis and periodontal tissue regeneration

Abstract

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.

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Funding

National Natural Science Foundation of China (National Science Foundation of China)(82371020)

the Project of State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration (2024MS04) the Shaanxi Provincial Health Research and Innovation Platform Construction Plan (2024PT-04)

Young Science and Technology Rising Star Project of Shaanxi Province, 2024ZC-KJXX-122 Rapid Response Research projects, 2023KXKT090

National Key Research and Development Program of China, 2022YFA1104400

the "Rapid Response" Research projects (2023KXKT017)

Intramural Research Program project founded by Fourth Military Medical University (2024QMJJ008)

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