Therapeutic potential of NGF-enriched extracellular vesicles in modulating neuroinflammation and enhancing peripheral nerve remyelination.

Neurological damage caused by peripheral nerve injury can be devastating and is a common neurological disorder that, along with muscle disorders, reduces the quality of life. Neural crest cells (NCCs) are a transient cell population that occurs during embryogenesis, can differentiate into various cells upon transplantation, and has potential therapeutic effects on neurological diseases. However, there are limitations to cell therapy, such as uncontrolled differentiation and tumor formation. Extracellular vesicles (EVs), which are non-cellular potential therapeutic candidates, are nanosized membrane-bound vesicles. Studies have been reported using starch cells derived from neural cells, such as neural stem cells, because they are involved in cell-to-cell communication and carry a variety of bioactive molecules. We investigated the effects of EVs isolated from NCCs on neuronal cell death and inflammation. Additionally, we overexpressed the nerve growth factor (NGF), which is involved in neural cell growth and proliferation, in NCCs to further investigate the effects of EVs containing NGF. NCC(oe-NGF)-EVs showed neuroprotective and regenerative properties by modulating inflammatory pathway, promoting Schwann cell activation, and enhancing remyelination. In vitro studies on NCC(oe-NGF)-EVs suppressed pro-inflammatory cytokines and reduced oxidative stress-induced neuronal apoptosis through NF-κB pathway inhibition and ERK, AKT signal activation. We also evaluated the effect of EVs on neuropathy by performing in vivo study. Our results suggest that NCC(oe-NGF)-EV had neuroprotective effects by reducing neuronal apoptosis and promoting neuronal proliferation based on neurite outgrowth and anti-inflammation effects treated with NCC(oe-NGF)-EVs. In addition, NCC(oe-NGF)-EVs were protected muscle loss caused by peripheral nerve injury. NCC(oe-NGF)-EV induced regeneration of damaged nerves and inhibited cell death through anti-inflammatory effects. This study suggests the potential of NGF-enriched EVs as non-cellular therapeutic platform for peripheral neuropathies and other neuroinflammatory disorders.