Peripheral nerve-derived extracellular vesicles are dynamically regulated in chemotherapy-induced painful peripheral neuropathy

Communication between Schwann cells (SCs) and other cells in the peripheral nerve remains incompletely understood. Extracellular vesicles (EVs) are important mediators of cell-cell communication, however, understanding the function of EVs in vivo is challenging in part because of difficulty in determining the cell type from which EVs originate. To identify SC EVs in vivo, we created a novel P0-Cre-turbo-GFP/human-CD9-EV reporter mouse. EVs were isolated from sciatic nerves without disrupting cell integrity. SC-derived EVs were identified by high-resolution microscopy and fluorescence nanoparticle tracking analyses. To test whether sciatic nerve EV (snEV) populations are regulated under neuropathological conditions, we treated mice with the chemotherapy agent, paclitaxel, which induces neuropathic pain. Proteomes of healthy and neuropathic snEVs differed as determined by LC-MS/MS. Proteins essential for maintenance of axonal integrity and SC myelination were identified selectively in healthy snEVs, whereas neuropathic snEVs contained increased levels of metabolic enzymes and receptors associated with neuronal excitability. Neuropathic snEVs contained diminished levels of EVs derived from SCs. These EVs differed in size from normal snEVs and triggered altered cell-signaling responses in sensory neurons. The appearance of neuropathic EVs correlated with the development of pain-related behaviors. Our findings demonstrate that peripheral nerve EV physiology is dynamically regulated in peripheral neuropathy.