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Retinal pigment epithelium extracellular vesicles are potent inducers of age-related macular degeneration disease phenotype in the outer retina
Marzena Kurzawa-Akanbi 1, Phillip Whitfield 2, Florence Burté 1, Pietro Maria Bertelli 3, Varun Pathak 3, Mary Doherty 4, Birthe Hilgen 1, Lina Gliaudelytė 5, Mark Platt 6, Rachel Queen 1, Jonathan Coxhead 1, Andrew Porter 1, Maria Öberg 7 8, Daniela Fabrikova 7 8, Tracey Davey 9, Chia Shyan Beh 1, Maria Georgiou 1, Joseph Collin 1, Veronika Boczonadi 1, Anetta Härtlova 7 8 10, Michael Taggart 1, Jumana Al-Aama 11, Viktor I Korolchuk 1, Christopher M Morris 5, Jasenka Guduric-Fuchs 3, David H Steel 1, Reinhold J Medina 3, Lyle Armstrong 1, Majlinda Lako 1
...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.