ABSTRACT
Extracellular vesicles from skin-derived precursor Schwann cells (SKP-SC-EVs) promote neurite outgrowth in culture and enhance peripheral nerve regeneration in rats. This study aimed at expanding the application of SKP-SC-EVs in nerve grafting by creating a chitosan/PLGA-based, SKP-SC-EVs-containing tissue engineered nerve graft (TENG) to bridge a 40-mm long sciatic nerve defect in dogs. SKP-SC-EVs contained in TENGs significantly accelerated the recovery of hind limb motor and electrophysiological functions, supported the outgrowth and myelination of regenerated axons, and alleviated the denervation-induced atrophy of target muscles in dogs. To clarify the underlying molecular mechanism, we observed that SKP-SC-EVs were rich in a variety of miRNAs linked to the axon growth of neurons, and miR-30b-5p was the most important among others. We further noted that miR-30b-5p contained within SKP-SC-EVs exerted nerve regeneration-promoting effects by targeting the Sin3a/HDAC complex and activating the phosphorylation of ERK, STAT3 or CREB. Our findings suggested that SKP-SC-EVs-incorporating TENGs represent a novel type of bioactive material with potential application for peripheral nerve repair in the clinic.
ABSTRACT
BACKGROUND: Repair of long-distance peripheral nerve defects remains an important clinical problem. Nerve grafts incorporated with extracellular vesicles (EVs) from various cell types have been developed to bridge peripheral nerve defects. In our previous research, EVs obtained from skin-derived precursor Schwann cells (SKP-SC-EVs) were demonstrated to promote neurite outgrowth in cultured cells and facilitate nerve regeneration in animal studies. METHODS: To further assess the functions of SKP-SC-EVs in nerve repair, we incorporated SKP-SC-EVs and Matrigel into chitosan nerve conduits (EV-NG) for repairing a 15-mm long-distance sciatic nerve defect in a rat model. Behavioral analysis, electrophysiological recording, histological investigation, molecular analysis, and morphometric assessment were carried out. RESULTS: The results revealed EV-NG significantly improved motor and sensory function recovery compared with nerve conduits (NG) without EVs incorporation. The outgrowth and myelination of regenerated axons were improved, while the atrophy of target muscles induced by denervation was alleviated after EVs addition. CONCLUSION: Our data indicated SKP-SC-EVs incorporation into nerve grafts represents a promising method for extended peripheral nerve damage repair.
