Extracellular vesicles from skin precursor-derived Schwann cells promote axonal outgrowth and regeneration of motoneurons via Akt/mTOR/p70S6K pathway.

BACKGROUND

Skin precursor-derived Schwann cells (SKP-SCs) have been shown to benefit the recovery of spinal cord injury (SCI) and peripheral nerve injury (PNI) with motor dysfunction. However, the effect of extracellular vesicles (EVs) from SKP-SCs responsible for neuroregeneration remains unknown.

METHODS

Based on the obtainment and identification of rat SKP-SCs and their derived EVs, the primary rat injury model of motoneurons resulting from axotomy or nerve crush , as well as the secondary rat ischemic hypoxic injury model of motoneuron exposure to oxygen-glucose-deprivation (OGD) , were treated with EVs from skin precursor-derived Schwann cells (SKP-SC-EVs), respectively. Then, the axonal outgrowth and regrowth was observed and compared, and cell viability as well as the protein kinase B/mammalian target of rapamycin/p70 S6 kinase (Akt/mTOR/p70S6K) signaling pathway was detected, moreover, rapamycin (an mTOR inhibitor) was used to further reveal the underlying molecular mechanism.

RESULTS

The internalization of SKP-SC-EVs by neuronal cells was identified and . Besides the pro-axonal outgrowth effect of SKP-SC-EVs, prospectively, the treatment of OGD-injured motoneurons with SKP-SC-EVs potentiated the restoration of neuronal viability and axonal regrowth. Furthermore, the axotomizing injury could be improved with SKP-SC-EVs treatment and . Finally, it was shown that the application of SKP-SC-EVs could activate the Akt/mTOR/p70S6K signaling pathway that can be abolished by rapamycin.

CONCLUSIONS

In summary, the addition of SKP-SC-EVs could regulate the cell growth and death signaling pathway mediated by Akt/mTOR/p70S6K, owing to the transmission of cargos in EVs to damaged motoneurons, which leads to axonal regrowth and neuronal resurrection. Thus, SKP-SC-EVs treatment could be a novel promising strategy for improving the axonal outgrowth and regeneration of motoneurons.