An Induced Pluripotent Stem Cell Patient Specific Model of Complement Factor H (Y402H) Polymorphism Displays Characteristic Features of Age‐Related Macular Degeneration and Indicates a Beneficial Role for UV Light Exposure. (9th October 2017)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Stem cells. Volume 35:Number 11(2017:Nov.)
• Page Start: 2305
• Page End: 2320
• Publication Date: 2017-10-09
• Subjects: Age‐related macular degeneration -- Complement factor H -- Induced pluripotent stem cell -- Retinal pigment epithelium; Cloning -- Periodicals; Clone cells -- Periodicals; Stem cells -- Periodicals; Cell Differentiation -- Periodicals; Cell Division -- Periodicals; Clone Cells -- Periodicals; Hematopoietic Stem Cells -- Periodicals; Stem Cells -- Periodicals; 571.84
• DOI: 10.1002/stem.2708
• Languages: English
• ISSNs: 1066-5099

Abstract

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 polymorphism in exon 9 (Y402H) has shown a strong association with susceptibility to AMD resulting in complement activation, recruitment of phagocytes, RPE damage, and visual decline. We have derived and characterized induced pluripotent stem cell (iPSC) lines from two subjects 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, factor I, and factor H‐like protein 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. Stem Cells 2017;35:2305–2320 Abstract : High risk donors had large APOE/C5b‐9 and lipid deposits, fewer mitochondria which were larger than in low risk donors. Microvilli on the surface were also smaller than in low risk donors. 390‐410 nm near UV light had a beneficial effect on high risk AMD‐RPE cells and improved the disease phenotype.