Schwann cell-derived extracellular vesicles promote periodontal tissue regeneration

Abstract Periodontitis is a common chronic inflammatory disease worldwide, and conventional therapies control inflammation but fail to achieve predictable regeneration. The inferior alveolar nerve (IAN) is a key peripheral nerve that governs mandibular bone homeostasis, and its disruption precipitates bone metabolic imbalance and impaired repair. However, the dynamic behavior of Schwann cells (SCs), the principal glial cells of this neural axis, and their mechanistic influence on periodontal ligament stem cells (PDLSCs) remain elusive. We established a rat IAN transection model and found that denervation induced progressive alveolar bone deterioration and compromised the osteogenic capacity of resident PDLSCs. Correlation analyses revealed that this bone deterioration coincided with progressive SC depletion in periodontal tissue, suggesting a link between Schwann cell loss and PDLSC dysfunction. Transcriptomic profiling of denervated PDLSCs revealed that dysregulated AMPK/mTOR signaling and suppressed autophagy are mechanisms underlying osteogenic impairment. Co-culture with SCs restored PDLSC proliferation and osteogenic differentiation, with SC-derived extracellular vesicles (SC-EVs) as important paracrine mediators of this effect. Mechanistically, SC-EVs delivered rno-miR-210-5p, which targeted the DAP1 gene and suppressed its expression, thereby activating the AMPK/mTOR-autophagy axis and rescuing osteogenic potential. In a rat denervated mandibular defect model, SC-EVs significantly enhanced bone regeneration. Collectively, these findings suggest that Schwann cells and their EVs participate in the neural regulation of periodontal bone metabolism and may play an important role in periodontal regeneration.