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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 and Collin, Joseph and Bojic, Sanja and Chichagova, Valeria and Buskin, Adriana and Xu, Yaobo and Lafage, Lucia and Otten, Elsje. G. and Anyfantis, George and Mellough, Carla and Przyborski, Stefan and Alharthi, Sameer and Korolchuk, Viktor and Lotery, Andrew and Saretzki, Gabriele and McKibbin, Martin and Armstrong, Lyle and Steel, David and Kavanagh, David and Lako, Majlinda (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). pp. 2305-2320.

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.

Item Type:Article
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Status:Peer-reviewed
Publisher Web site:https://doi.org/10.1002/stem.2708
Publisher statement:© 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.
Date accepted:07 September 2017
Date deposited:09 October 2017
Date of first online publication:09 October 2017
Date first made open access:No date available

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