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An iPSC Patient Specific Model of CFH (Y402H) Polymorphism Displays Characteristic Features of AMD and Indicates a Beneficial Role for UV Light Exposure

Hallam, Dean; Collin, Joseph; Bojic, Sanja; Chichagova, Valeria; Buskin, Adriana; Xu, Yaobo; Lafage, Lucia; Otten, Elsje. G.; Anyfantis, George; Mellough, Carla; Przyborski, Stefan; Alharthi, Sameer; Korolchuk, Viktor; Lotery, Andrew; Saretzki, Gabriele; McKibbin, Martin; Armstrong, Lyle; Steel, David; Kavanagh, David; Lako, Majlinda

An iPSC Patient Specific Model of CFH (Y402H) Polymorphism Displays Characteristic Features of AMD and Indicates a Beneficial Role for UV Light Exposure Thumbnail


Authors

Dean Hallam

Joseph Collin

Sanja Bojic

Valeria Chichagova

Adriana Buskin

Yaobo Xu

Lucia Lafage

Elsje. G. Otten

George Anyfantis

Carla Mellough

Sameer Alharthi

Viktor Korolchuk

Andrew Lotery

Gabriele Saretzki

Martin McKibbin

Lyle Armstrong

David Steel

David Kavanagh

Majlinda Lako



Abstract

Age related macular degeneration (AMD) is the most common cause of blindness, accounting for 8.7% of all blindness globally. Vision loss is caused ultimately by apoptosis of the retinal pigment epithelium (RPE) and overlying photoreceptors. Treatments are evolving for the wet form of the disease, however these do not exist for the dry form. Complement factor H (CFH) polymorphism in exon 9 (Y402H) has shown a strong association with susceptibility to AMD resulting in complement activation, recruitment of phagocytes, retinal pigment epithelium (RPE) damage and visual decline. We have derived and characterised induced pluripotent stem cell (iPSCs) lines from two patients without AMD and low risk genotype and two patients with advanced AMD and high risk genotype and generated RPE cells that show local secretion of several proteins involved in the complement pathway including factor H (FH), factor I (FI) and factor H like 1 (FHL-1). The iPSC RPE cells derived from high risk patients mimic several key features of AMD including increased inflammation and cellular stress, accumulation of lipid droplets, impaired autophagy and deposition of “drüsen” like deposits. The low and high risk RPE cells respond differently to intermittent exposure to UV light which leads to an improvement in cellular and functional phenotype only in the high risk AMD-RPE cells. Taken together our data indicate that the patient specific iPSC model provides a robust platform for understanding the role of complement activation in AMD, evaluating new therapies based on complement modulation and drug testing.

Citation

Hallam, D., Collin, J., Bojic, S., Chichagova, V., Buskin, A., Xu, Y., …Lako, M. (2017). An iPSC Patient Specific Model of CFH (Y402H) Polymorphism Displays Characteristic Features of AMD and Indicates a Beneficial Role for UV Light Exposure. Stem Cells, 35(11), 2305-2320. https://doi.org/10.1002/stem.2708

Journal Article Type Article
Acceptance Date Sep 7, 2017
Online Publication Date Oct 9, 2017
Publication Date Oct 9, 2017
Deposit Date Oct 5, 2017
Publicly Available Date Mar 29, 2024
Journal STEM CELLS
Print ISSN 1066-5099
Electronic ISSN 1549-4918
Publisher Oxford University Press
Peer Reviewed Peer Reviewed
Volume 35
Issue 11
Pages 2305-2320
DOI https://doi.org/10.1002/stem.2708

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Published Journal Article (Advance online version) (1.3 Mb)
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Publisher Licence URL
http://creativecommons.org/licenses/by/4.0/

Copyright Statement
Advance online version © 2017 The Authors STEM CELLS published by
Wiley Periodicals, Inc. on behalf of AlphaMed Press This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.







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