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

Age-related macular degeneration (AMD) is a leading cause of blindness. Vision loss is caused by the loss of the retinal pigment epithelium (RPE) and photoreceptors and/or retinal and choroidal angiogenesis. Here we use AMD patient specific RPE cells with the Y402H high-risk polymorphism in the complement factor H to perform a comprehensive analysis of EVs, their cargo and role in disease pathology. We show that AMD RPE is characterised by enhanced and polarised EV secretion. Transcriptomic, proteomic and lipidomic analyses demonstrate that AMD RPE EVs carry RNA, proteins and lipids that reflect changes in the parental RPE and mediate key AMD pathological processes including oxidative stress, cytoskeletal dysfunction, angiogenesis and drusen accumulation. We demonstrate that exposure of control RPE to AMD RPE apical EVs leads to the formation of stress vacuoles, cytoskeletal destabilization, and abnormalities in the morphology of the nucleus in the recipient cells. Treatment of retinal organoids with apical AMD RPE EVs leads to disrupted neuroepithelium and appearance of cytoprotective alpha B crystallin immunopositive cells, with some co-expressing retinal progenitor cell markers Pax6 or Vsx2, suggesting activation of regenerative pathways upon injury. These findings indicate that AMD RPE EVs mediated signalling have an important role in disease progression.