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

ABSTRACT: 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.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Majlinda Lako

PROVIDER: MSV000088713 | MassIVE | Fri Jan 21 07:17:00 GMT 2022

SECONDARY ACCESSION(S): PXD031135

REPOSITORIES: MassIVE

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

Kurzawa-Akanbi Marzena M Whitfield Phillip P Burté Florence F Bertelli Pietro Maria PM Pathak Varun V Doherty Mary M Hilgen Birthe B Gliaudelytė Lina L Platt Mark M Queen Rachel R Coxhead Jonathan J Porter Andrew A Öberg Maria M Fabrikova Daniela D Davey Tracey T Beh Chia Shyan CS Georgiou Maria M Collin Joseph J Boczonadi Veronika V Härtlova Anetta A Taggart Michael M Al-Aama Jumana J Korolchuk Viktor I VI Morris Christopher M CM Guduric-Fuchs Jasenka J Steel David H DH Medina Reinhold J RJ Armstrong Lyle L Lako Majlinda M

Journal of extracellular vesicles 20221201 12

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-omi ...[more]

PMID: 36544284

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