TY - JOUR
T1 - Retinal pigment epithelium extracellular vesicles are potent inducers of age‐related macular degeneration disease phenotype in the outer retina
AU - Kurzawa‐Akanbi, Marzena
AU - Whitfield, Phillip
AU - Burté, Florence
AU - Bertelli, Pietro Maria
AU - Pathak, Varun
AU - Doherty, Mary
AU - Hilgen, Birthe
AU - Gliaudelytė, Lina
AU - Platt, Mark
AU - Queen, Rachel
AU - Coxhead, Jonathan
AU - Porter, Andrew
AU - Öberg, Maria
AU - Fabrikova, Daniela
AU - Davey, Tracey
AU - Beh, Chia Shyan
AU - Georgiou, Maria
AU - Collin, Joseph
AU - Boczonadi, Veronika
AU - Härtlova, Anetta
AU - Taggart, Michael
AU - Al‐Aama, Jumana
AU - Korolchuk, Viktor I
AU - Morris, Christopher M
AU - Guduric‐Fuchs, Jasenka
AU - Steel, David H
AU - Medina, Reinhold J
AU - Armstrong, Lyle
AU - Lako, Majlinda
PY - 2022/12/21
Y1 - 2022/12/21
N2 - 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.
AB - 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.
KW - Extracellular Vesicles - metabolism
KW - Humans
KW - Macular Degeneration - metabolism
KW - Phenotype
KW - Retina - metabolism - pathology
KW - Retinal Pigment Epithelium - metabolism
KW - age-related macular degeneration
KW - complement factor H
KW - extracellular vesicles
KW - human induced pluripotent stem cells
KW - photoreceptors
KW - retina
KW - retinal pigment epithelium
U2 - 10.1002/jev2.12295
DO - 10.1002/jev2.12295
M3 - Article
SN - 2001-3078
VL - 11
JO - Journal of Extracellular Vesicles
JF - Journal of Extracellular Vesicles
IS - 12
M1 - 12295
ER -