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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, Professor Viktor KorolchukORCiD, Dr Christopher Morris, Professor David SteelORCiD, Professor Lyle Armstrong, Professor Majlinda LakoORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 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.
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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