GMSC-Extracellular Vesicles Activate Schwann Cell Repair Phenotype and Promote Nerve Regeneration.

A fully functional recovery of peripheral nerve injury remains a major challenge and an unmet clinical need. Recent evidence has reported promising therapeutic effects of mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) in experimental models of tissue injuries and inflammatory diseases, but less is known about their effects on peripheral nerve regeneration. Here, we investigated the effects of GMSC-derived EVs on peripheral nerve regeneration of crush-injured mice sciatic nerves. In vivo studies mimicking clinical nerve repair showed that locally wrapping gelfoam embedded with GMSC-derived EVs at the crush injury site promoted functional recovery and axonal regeneration, which were comparable to effects conferred by direct transplantation of GMSCs. Mechanistically, we showed that GMSC-derived EVs promoted proliferation and migration of Schwann cells, upregulated the protein expressions of c-JUN, Notch1, GFAP, and SOX2, characteristic genes of dedifferentiation or repair phenotype of Schwann cells, whereby pharmacologically blocking c-JUN/JNK activity significantly abrogated GMSC-derived EV induced upregulation of these Schwann cell dedifferentiation/repair phenotype-related genes. These findings suggest that GMSC-derived EVs promote peripheral nerve regeneration possibly by activating c-JUN-governed repair phenotype of Schwann cells.