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

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

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2305-2320
Number of pages16
JournalStem Cells
Volume35
Issue number11
DOIs
Publication statusPublished - 1 Nov 2017
Externally publishedYes

Fingerprint

Complement Factor H
Induced Pluripotent Stem Cells
Macular Degeneration
Ultraviolet Rays
Retinal Pigment Epithelium
Complement Activation
Blindness
Genotype
Autophagy
Phagocytes
Exons
Proteins
Stem Cells
Apoptosis
Inflammation
Phenotype
Cell Line
Therapeutics
Pharmaceutical Preparations

Cite this

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 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. In: Stem Cells. 2017 ; Vol. 35, No. 11. pp. 2305-2320.
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title = "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",
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 “dr{\"u}sen”-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.",
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Hallam, D, Collin, J, Bojic, S, Chichagova, V, Buskin, A, Xu, Y, Lafage, L, Otten, EG, Anyfantis, G, Mellough, C, Przyborski, S, Alharthi, S, Korolchuk, V, Lotery, A, Saretzki, G, McKibbin, M, Armstrong, L, Steel, D, Kavanagh, D & Lako, M 2017, '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' Stem Cells, vol. 35, no. 11, pp. 2305-2320. https://doi.org/10.1002/stem.2708

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. / 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.

In: Stem Cells, Vol. 35, No. 11, 01.11.2017, p. 2305-2320.

Research output: Contribution to journalArticle

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AU - Hallam, Dean

AU - Collin, Joseph

AU - Bojic, Sanja

AU - Chichagova, Valeria

AU - Buskin, Adriana

AU - Xu, Yaobo

AU - Lafage, Lucia

AU - Otten, Elsje G.

AU - Anyfantis, George

AU - Mellough, Carla

AU - Przyborski, Stefan

AU - Alharthi, Sameer

AU - Korolchuk, Viktor

AU - Lotery, Andrew

AU - Saretzki, Gabriele

AU - McKibbin, Martin

AU - Armstrong, Lyle

AU - Steel, David

AU - Kavanagh, David

AU - Lako, Majlinda

PY - 2017/11/1

Y1 - 2017/11/1

N2 - 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.

AB - 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.

KW - Age-related macular degeneration

KW - Complement factor H

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KW - Retinal pigment epithelium

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