Human induced pluripotent stem cell-derived extracellular vesicles promote neuroprotection effects in rat optic nerve crush model

Abstract

Optic neuropathies significantly contribute to permanent vision loss, frequently characterized by the deterioration of retinal ganglion cells (RGCs) and axonal loss. Current therapeutic strategies remain insufficient. Induced pluripotent stem cell-derived extracellular vesicles (iPSC-EVs) have surfaced as a compelling substitute for stem cell therapies. Our study evaluates the neuroprotective effects of iPSC-EVs in a rat optic nerve crush (ONC) model. iPSC-EVs were isolated and characterized. The intravitreal (IVT) injections of iPSC-EVs or PBS were performed. RGCs survival was assessed at 7 and 14 days post-injury. Axonal regeneration was evaluated via anterograde labeling. Apoptosis of RGCs was detected using TUNEL assay. Retinal morphological changes and visual function recovery were assessed. Transcriptomic changes in the retina were analyzed by RNA sequencing to investigate potential underlying mechanisms. Additionally, Western blot was conducted to evaluate the expression levels of components in the phosphatidylinositol 3-kinases/protein kinase B (PI3K/AKT) pathway. The IVT injections of iPSC-EVs significantly improved RGCs survival and reduced neuronal apoptosis. Optical coherence tomography (OCT) revealed preservation of retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC) thickness, alongside reduced optic nerve atrophy. Functional recovery was evidenced by F-VEP and axonal regeneration was detected. Mechanistically, RNA sequencing and Western blot implicated the stimulation of the PI3K/AKT pathway. Our study shows that iPSC-EVs exert significant neuroprotective and regenerative effects in a rat ONC model, underscoring their promise as a novel treatment candidate for optic neuropathies.