Astrocyte-Derived Extracellular Vesicles Alleviate Optic Nerve Injury Through Remodeling of Retinal Microenvironmental Homeostasis.

Purpose: Traumatic optic neuropathy (TON) leads to the loss of retinal ganglion cells (RGCs) and results in permanent visual impairment. Protecting and regenerating RGCs is crucial for the treatment of TON. Studies have demonstrated that astrocyte-derived extracellular vesicles (ADEVs) exhibit neuroprotective effects in models of central nervous system (CNS) injury. This study aimed to investigate whether ADEVs have a similar neuroprotective effect on RGCs in an optic nerve crush (ONC) rat model. Methods: ADEVs were collected from primary rat astrocytes, and an ONC model was established to evaluate the effects of ADEVs on retinal structure and visual function using optical coherence tomography (OCT), hematoxylin and eosin (H&E) staining, and flash visual evoked potential (f-VEP) analysis. Immunofluorescence was used to examine RGCs and investigate reactive gliotic changes. Additionally, miRNA sequencing of ADEVs and retinal mRNA sequencing were performed to identify the potential mechanisms involved. Results: ADEVs protected RGCs from progressive loss and improved visual function. ADEVs also significantly increased the expression of glial fibrillary acidic protein (GFAP) and modulated microglial activation. The miRNAs associated with ADEVs were targeted by neuroprotective signals, such as MAPK, PI3K-AKT, and TNF-α, and through the targeting network generated via retinal mRNA sequencing, we found that potential functional genes, such as THBS1, PAK3, and Gstm1, likely participate in microenvironmental regulation. Conclusions: We discovered that ADEVs play a neuroprotective role in optic nerve injury. Our findings provide a new cell-free therapeutic strategy for optic neuropathy.