Retinal pigment epithelium extracellular vesicles are potent inducers of age‐related macular degeneration disease phenotype in the outer retina

Abstract

Age-related macular degeneration (AMD) is a leading cause of blindness. Vision loss is caused by the retinal pigment epithelium (RPE) and photoreceptors atrophy and/or retinal and choroidal angiogenesis. Here we use AMD patient-specific RPE cells with the Complement Factor H Y402H high-risk polymorphism to perform a comprehensive analysis of extracellular vesicles (EVs), their cargo and role in disease pathology. We show that AMD RPE is characterised by enhanced polarised EV secretion. Multi-omics analyses demonstrate that AMD RPE EVs carry RNA, proteins and lipids, which mediate key AMD features including oxidative stress, cytoskeletal dysfunction, angiogenesis and drusen accumulation. Moreover, AMD RPE EVs induce amyloid fibril formation, revealing their role in drusen formation. WeThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Extracellular vesicles: an emerging player in retinal homeostasis

“…In demonstrating drusen-associated proteins are secreted in exosomes from RPE cells, Flores-Bellver et al, 2021., rationalized interrogating a causal role of RPE-secreted exosomes in promoting AMD pathophysiology. Consistently, a recent study (Kurzawa-Akanbi et al, 2022) showed that supplementation of control iPSC-RPE cultures with AMD iPSC-RPE-secreted apical EVs is independently sufficient to cause AMD-associated features such as stress vacuoles, cytoskeletal destabilization and abnormal morphology of the nucleus in control iPSC-RPE cells. Furthermore, this study documented a vast difference in the transcriptomic, proteomic and lipidomic profile of EVs released by control iPSC-RPE and AMD iPSC-RPE cells (Kurzawa-Akanbi et al, 2022).…”

Rescuing Photoreceptors in RPE Dysfunction-Driven Retinal Degeneration: The Role of Small Extracellular Vesicles Secreted from Retinal Pigment Epithelium

“…Furthermore, recent studies have revealed that the RPE secretes distinct EV from its apical side towards the photoreceptors and from its basal side towards the choroid. 27-29 Therefore, our study findings, alongside the enriched lipid-enriched composition of EVs and the emerging understanding of the role of RPE-secreted EVs, suggest a potentially substantial contribution to lipid homeostasis between the RPE and photoreceptor cells, thereby influencing overall retinal health. Further investigation is essential to fully comprehend the potential therapeutic implications of RPE-secreted EVs, especially in regulating lipid metabolism amidst the progression of retinal degenerative conditions.…”

Autophagy Activation Promoted by Pulses of Light and Phytochemicals Counteracting Oxidative Stress during Age-Related Macular Degeneration

“…It is remarkable that EVs derived from AMD-RPE may induce aggregation of amyloid fibrils and drusen formation. In fact, as reported by Kurzawa-Akanbi et al [ 61 ], when control RPE is exposed to AMD-RPE, apical EVs may shift the phenotype of control RPE towards AMD-RPE. In fact, control RPE exposed to AMD-derived EVs develops stress vacuoles, cytoskeletal destabilization and morphological abnormalities.…”