Macrophage reprogramming orchestrates neuro-bone coupling in jaw repair
Description
The maxillofacial skeleton is densely innervated, but how injury initiates neuro-osteogenic coupling is unclear. Using cross-system single‑cell transcriptomics and macrophage‑specific Rab27a knockout mice to impair EV secretion, we show that macrophage‑derived extracellular vesicles (Mφ‑EVs) are essential for linking immune activation to skeletal repair. Mechanistically, pantothenic acid (vitamin B5) enriched in injury‑responsive Mφ‑EVs is transferred to Schwann cells, enhancing mitochondrial metabolism and NDUFAB1 production, which subsequently acts on bone marrow mesenchymal stem cells to restore oxidative phosphorylation and osteogenic differentiation. EV blockade markedly impairs regeneration, whereas exogenous pantothenic acid supplementation rescues the defect. Collectively, our findings define a macrophage–Schwann cell–BMMSC metabolic relay that initiates neuro‑osteogenic coupling during craniofacial bone repair and identify EV‑associated pantothenic acid as a potential therapeutic strategy for enhancing skeletal regeneration.