Exosomes from Microglia Attenuate Photoreceptor Injury and Neovascularization in an Animal Model of Retinopathy of Prematurity

Abstract

The role of microglia in the pathophysiology of ischemic retinal diseases has been studied extensively. Exosomes from microglial cells exert protective effects during several nervous system diseases, but their roles in hypoxia-induced retinopathy remain unclear. In our study, exosomes derived from microglial cells were injected into the vitreous body of mice with oxygen-induced retinopathy (OIR). Results showed that exosome-treated OIR mice exhibited smaller avascular areas and fewer neovascular tufts in addition to decreased vascular endothelial growth factor (VEGF) and transforming growth factor β (TGF-β) expression. Moreover, photoreceptor apoptosis was suppressed by exosome injection. Mechanistically, exosomes from microglial cells were incorporated into photoreceptors in vitro and inhibited the inositol-requiring enzyme 1α (IRE1α)-X-box binding protein 1 (XBP1) cascade, which contributes to hypoxia-induced photoreceptor apoptosis. Furthermore, the exosomes also downregulated the mRNA and protein levels of VEGF and TGF-β in hypoxia-exposed photoreceptors. A microRNA assay showed that microRNA-24-3p (miR-24-3p) levels were extremely high in exosomes from microglial cells, suggesting that this could be the key molecule that inhibits the hypoxia-induced expression of IRE1α in photoreceptors. These findings delineate a novel exosome-mediated mechanism of microglial cell-photoreceptor crosstalk that facilitates normal angiogenesis and visual function in OIR mice; thus, our results also suggest a potential therapeutic approach for retinopathy of prematurity.

Extracellular Vesicles and MicroRNA: Putative Role in Diagnosis and Treatment of Diabetic Retinopathy

“…Nonetheless, in the early stages of the disease, EVs can also exhibit protective effects, preventing the rapid progression of the retinal damage. For example, in vitro and in vivo studies have demonstrated that EVs derived from microglial cells were able to inhibit hypoxia-induced photoreceptor apoptosis, thus preventing neovascularization and alleviating visual injury [76].…”

Extracellular vesicles and their miRNA cargo in retinal health and degeneration: mediators of homeostasis, and vehicles for targeted gene therapy

“…As CCL2 has been implicated as a key chemokine in the pathogenesis of multiple retinal degenerative diseases (Newman, Gallo et al 2012, Rutar, Natoli et al 2012, Zuzic, Rojo Arias et al 2019, and is a known target of miR-124-3p (Zuzic, Rojo Arias et al 2019); exosome-based therapies that replenish retinal levels of this miRNA may prove efficacious as a possible therapeutic, as evidenced in other works (Chu-Tan, ). In addition, exosomes derived from microglial cells and injected into the vitreous of mice subjected to oxygen-induced retinopathy showed protective effects, reducing avascular regions in the retina, VEGF expression, and photoreceptor apoptosis, compared to controls (Xu, Wu et al 2019). It was hypothesized by these authors that exosomal-miR-24-3p mediated this protection against hypoxia-induced cell death (Xu, Wu et al 2019).…”

“…In addition, exosomes derived from microglial cells and injected into the vitreous of mice subjected to oxygen-induced retinopathy showed protective effects, reducing avascular regions in the retina, VEGF expression, and photoreceptor apoptosis, compared to controls (Xu, Wu et al 2019). It was hypothesized by these authors that exosomal-miR-24-3p mediated this protection against hypoxia-induced cell death (Xu, Wu et al 2019).…”

Extracellular Vesicles as a Potential Therapy for Neonatal Conditions: State of the Art and Challenges in Clinical Translation

“…Further evidence that EV therapy might be beneficial for retinal conditions derives from a recent study that employed microglial-derived exosomes [44]. The rationale behind the use of these exosomes in ROP is that microglial cells play a role in the innate immune response and normal vascular development of the retina [45,46].…”

“…The rationale behind the use of these exosomes in ROP is that microglial cells play a role in the innate immune response and normal vascular development of the retina [45,46]. Using an in vivo mouse model of oxygen-induced retinopathy, Xu et al showed that intravitreal administration of microglial-derived exosomes limited the central avascular area, reduced the area of retinal neovascularization, and decreased the expression of hypoxia-induced VEGF, which is considered the most important factor involved in the retinal neovascularization process [44]. Moreover, electroretinography data established better visual function in microglia-derived exosome-treated retinas [44].…”