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

Kurzawa‐Akanbi, M. et al. (2022) Retinal pigment epithelium extracellular vesicles are potent inducers of age‐related macular degeneration disease phenotype in the outer retina. Journal of Extracellular Vesicles, 11(12), 12295. (doi: 10.1002/jev2.12295)

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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.

Item Type:Articles
Additional Information:Funding information: Macular Society UK, MRC Confidence in Concept, Dunhill Medical Trust RPFG 1910/199, MRC MR/S036695/1, BBSRC BB/T000805/1, Diabetes UK 20/0006162, Knut and Alice Wallenberg Foundation University of Gothenburg Sweden, Styrelsen för Wilhelm och Martina Lundgrens Vetenskapsfond; 2019-3205, 2020-3634. EMRS is supported by BBSRC (BB/R013942/1).
Glasgow Author(s) Enlighten ID:Whitfield, Professor Phil
Authors: Kurzawa‐Akanbi, M., Whitfield, P., Burté, F., Bertelli, P. M., Pathak, V., Doherty, M., Hilgen, B., Gliaudelytė, L., Platt, M., Queen, R., Coxhead, J., Porter, A., Öberg, M., Fabrikova, D., Davey, T., Beh, C. S., Georgiou, M., Collin, J., Boczonadi, V., Härtlova, A., Taggart, M., Al‐Aama, J., Korolchuk, V. I., Morris, C. M., Guduric‐Fuchs, J., Steel, D. H., Medina, R. J., Armstrong, L., and Lako, M.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Journal Name:Journal of Extracellular Vesicles
ISSN (Online):2001-3078
Published Online:21 December 2022
Copyright Holders:Copyright © 2022 The Authors
First Published:First published in Journal of Extracellular Vesicles 11(12): 12295
Publisher Policy:Reproduced under a Creative Commons License

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