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

Lookup NU author(s): Dr Marzena Kurzawa-Akanbi, Dr Florence Burte, Dr Birthe HilgenORCiD, Dr Rachel Queen, Dr Jonathan Coxhead, Dr Andrew Porter, Tracey DaveyORCiD, Dr Sze Yi Beh, Dr Maria Georgiou, Dr Joseph Collin, Dr Veronika Boczonadi, Professor Michael TaggartORCiD, Dr Viktor Korolchuk, Dr Christopher Morris, Professor David SteelORCiD, Professor Lyle Armstrong, Professor Majlinda LakoORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2022 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles.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.

Publication metadata

Author(s): Kurzawa-Akanbi M, Whitfield P, Burte F, Bertelli PM, Pathak V, Doherty M, Hilgen B, Gliaudelyte L, Platt M, Queen R, Coxhead J, Porter A, Oberg M, Fabrikova D, Davey T, Beh CS, Georgiou M, Collin J, Boczonadi V, Hartlova A, Taggart M, Al-Aama J, Korolchuk VI, Morris CM, Guduric-Fuchs J, Steel DH, Medina RJ, Armstrong L, Lako M

Publication type: Article

Publication status: Published

Journal: Journal of Extracellular Vesicles

Year: 2022

Volume: 11

Issue: 12

Print publication date: 21/12/2022

Online publication date: 21/12/2022

Acceptance date: 07/12/2022

Date deposited: 16/06/2023

ISSN (electronic): 2001-3078

Publisher: John Wiley and Sons Inc

URL: https://doi.org/10.1002/jev2.12295

DOI: 10.1002/jev2.12295

PubMed id: 36544284

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