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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. We demonstrate that exposure of control RPE to AMD RPE apical EVs leads to the acquisition of AMD features such as stress vacuoles, cytoskeletal destabilization and abnormalities in the morphology of the nucleus. Retinal organoid treatment with apical AMD RPE EVs leads to disrupted neuroepithelium and the appearance of cytoprotective alpha B crystallin immunopositive cells, with some co-expressing retinal progenitor cell markers Pax6/Vsx2, suggesting injury-induced regenerative pathways activation. These findings indicate that AMD RPE EVs are potent inducers of AMD phenotype in the neighbouring RPE and retinal cells.

SUBMITTER: Kurzawa-Akanbi M 

PROVIDER: S-EPMC9772497 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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

Kurzawa-Akanbi Marzena M   Whitfield Phillip P   Burté Florence F   Bertelli Pietro Maria PM   Pathak Varun V   Doherty Mary M   Hilgen Birthe B   Gliaudelytė Lina L   Platt Mark M   Queen Rachel R   Coxhead Jonathan J   Porter Andrew A   Öberg Maria M   Fabrikova Daniela D   Davey Tracey T   Beh Chia Shyan CS   Georgiou Maria M   Collin Joseph J   Boczonadi Veronika V   Härtlova Anetta A   Taggart Michael M   Al-Aama Jumana J   Korolchuk Viktor I VI   Morris Christopher M CM   Guduric-Fuchs Jasenka J   Steel David H DH   Medina Reinhold J RJ   Armstrong Lyle L   Lako Majlinda M  

Journal of extracellular vesicles 20221201 12


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-omi  ...[more]

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