Stage‐Specific Molecular Cargo of Schwann Cell–Derived Extracellular Vesicles is Associated With Peripheral Nerve Repair

ABSTRACT

Schwann cells (SCs) play a critical role in peripheral nerve regeneration, undergoing dynamic phenotype transitions from myelinating to repair stages following injury. While SC‐derived extracellular vesicles (SC‐EVs) have emerged as key mediators of intercellular communication during nerve repair, their stage‐specific molecular cargo and functional roles remained incompletely understood. Here, we delineate protein, microRNA and long non‐coding RNA (lncRNA) landscapes of SC‐EVs across distinct differentiation stages, including immature, myelinating, and repair phenotypes, using an in vitro model of primary rat SCs. We show that repair SC‐EVs carry distinct microRNAs predicted to modulate genes involved in myelin ensheathment, neuronal differentiation, and neurogenesis. Treatment of immature Schwann cells with repair SC‐EVs increased SOX2 expression, suggesting activation of repair‐associated Schwann cell responses. Furthermore, modulation of miR‐330‐5p, miRNA identified in repair SC‐EVs, altered SOX2 expression, Schwann cell proliferation, and migration. Repair SC‐EVs also contain lncRNAs that may bind and sequester miRNAs, potentially relieving repression of pro‐regenerative genes. These findings suggest possible mechanisms by which SC‐EVs may regulate Schwann cell repair functions and provide a molecular framework for mechanistic studies.