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An induced pluripotent stem cell patient specific model of CFH (Y402H) polymorphism displays characteristic features of AMD and indicates a beneficial role for UV light exposure

An induced pluripotent stem cell patient specific model of CFH (Y402H) polymorphism displays characteristic features of AMD and indicates a beneficial role for UV light exposure
An induced pluripotent stem cell patient specific model of CFH (Y402H) polymorphism displays characteristic features of AMD and indicates a beneficial role for UV light exposure
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. This article is protected by copyright. All rights reserved.
0250-6793
Hallam, Dean
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Collin, Joseph F.
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Bojic, Sanja
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Chichagova, Valeria
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Buskin, Adriana
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Anyfantis, Georgios
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Armstrong, Lyle
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Przyborski, Stefan
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Korolchuk, Viktor I
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Lotery, Andrew
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Saretzki, Gabriele
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McKibbin, Martin
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Steel, D.
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Chichagova, Valeria
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Xu, Yaobo
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Lafage, Lucia
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Mellough, Carla
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Alharthi, Sameer
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Kavanagh, D.
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Lako, Majlinda
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Hallam, Dean
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Collin, Joseph F.
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Bojic, Sanja
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Chichagova, Valeria
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Buskin, Adriana
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Anyfantis, Georgios
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Armstrong, Lyle
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Przyborski, Stefan
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Korolchuk, Viktor I
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Lotery, Andrew
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Saretzki, Gabriele
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McKibbin, Martin
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Steel, D.
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Chichagova, Valeria
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Xu, Yaobo
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Lafage, Lucia
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Mellough, Carla
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Alharthi, Sameer
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Kavanagh, D.
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Lako, Majlinda
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Hallam, Dean, Collin, Joseph F., Bojic, Sanja, Chichagova, Valeria, Buskin, Adriana, Anyfantis, Georgios, Armstrong, Lyle, Przyborski, Stefan, Korolchuk, Viktor I, Lotery, Andrew, Saretzki, Gabriele, McKibbin, Martin, Steel, D., Chichagova, Valeria, Xu, Yaobo, Lafage, Lucia, Mellough, Carla, Alharthi, Sameer, Kavanagh, D. and Lako, Majlinda (2017) An induced pluripotent stem cell 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). (doi:10.1002/stem.2708).

Record type: Article

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. This article is protected by copyright. All rights reserved.

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Accepted/In Press date: 7 September 2017
e-pub ahead of print date: 9 October 2017
Published date: November 2017

Identifiers

Local EPrints ID: 415507
URI: https://eprints.soton.ac.uk/id/eprint/415507
ISSN: 0250-6793
PURE UUID: ce4cf31b-5f20-4278-87ca-0190da230bc6
ORCID for Andrew Lotery: ORCID iD orcid.org/0000-0001-5541-4305

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Date deposited: 13 Nov 2017 17:30
Last modified: 03 Dec 2019 01:50

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Contributors

Author: Dean Hallam
Author: Joseph F. Collin
Author: Sanja Bojic
Author: Valeria Chichagova
Author: Adriana Buskin
Author: Georgios Anyfantis
Author: Lyle Armstrong
Author: Stefan Przyborski
Author: Viktor I Korolchuk
Author: Andrew Lotery ORCID iD
Author: Gabriele Saretzki
Author: Martin McKibbin
Author: D. Steel
Author: Valeria Chichagova
Author: Yaobo Xu
Author: Lucia Lafage
Author: Carla Mellough
Author: Sameer Alharthi
Author: D. Kavanagh
Author: Majlinda Lako

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