Exosomal PSMD1 Derived From Dental Pulp Mesenchymal Stem Cells Promotes Microglial M2 Polarization to Alleviate Spinal Cord Injury

BACKGROUND: Exosomes derived from mesenchymal stem cells (MSCs) and their cargo contribute to the protective properties of MSCs in spinal cord injury (SCI). This study aimed to explore the role of Proteasome 26S subunit non-ATPase 1 (PSMD1), delivered via exosomes derived from dental pulp mesenchymal stem cells (DPMSCs-Exo), in SCI repair. METHODS: Proteomic profiling was conducted to identify proteins enriched in DPMSCs-Exo. M1/M2 microglial polarization was assessed using flow cytometry, immunofluorescence, and western blotting. The apoptotic rates of BV2 microglia and NE-4C neural stem cells were measured by flow cytometry, whereas cell viability was determined using the CCK-8 assay. Western blotting was performed to analyze proteins involved in autophagy and apoptosis. Pro-inflammatory cytokine levels were quantified using ELISA. Additionally, a mouse SCI model treated with DPMSCs-Exo was established to assess therapeutic effects in vivo. RESULTS: DPMSCs-Exo enriched with PSMD1 suppressed M1-associated inflammatory activation, promoted M2 microglial polarization, and suppressed inflammation in BV2 cells following LPS exposure by activating the JAK2/STAT3 pathway. The shift toward an anti-inflammatory microglial phenotype indirectly enhanced survival, reduced apoptosis, and inhibited autophagy in NE-4C neural stem cells. In SCI mice, exosomal PSMD1 improved locomotor recovery, promoted spinal tissue regeneration at the injury site, reduced inflammation and astrocyte activation, and increased M2 microglial polarization. CONCLUSIONS: DPMSCs-Exo carrying PSMD1 suppressed M1-type inflammatory responses while promoting M2 microglial polarization, thereby attenuating inflammation and astrocyte activation and facilitating SCI repair. These findings suggest that DPMSCs-Exo may be a promising therapeutic candidate for the treatment of SCI.