Bioactive materials from berberine-treated human bone marrow mesenchymal stem cells accelerate tooth extraction socket healing through the jaw vascular unit.

Delayed tooth extraction socket (TES) healing can cause failure of subsequent oral implantation and increase socioeconomic burden on patients. Excessive amounts of M1 macrophages, apoptotic neutrophils (ANs), and neutrophil extracellular traps (NETs) impair alveolar bone regeneration during TES healing. In the present study, we first discovered that conditioned medium (CM) collected from berberine-treated human bone marrow mesenchymal stem cells (BBR-HB-CM) accelerated TES healing. BBR-HB-CM contained bioactive materials that promoted the polarization of macrophages from M1 to M2, impeded the formation of ANs and NETs, and modulated M2 macrophage efferocytosis in vivo and in vitro. Mechanistically, BBR-HB-CM promoted bone formation by inhibiting macrophage-myofibroblast transition and reprogrammed macrophage polarization through p85/AKT/mTOR pathway-dependent autophagy. The 3-methyladenine abolished the therapeutic effects of BBR-HB-CM. Further studies revealed that BBR-HB-CM accelerated TES healing in rats with type 2 diabetes mellitus. Overall, our results demonstrated that BBR-HB-CM had high potential to promote rapid TES healing.