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
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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.
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Dysfunctional FH, including the p.Y402H variant, can lead to overactivation of the complement system, which can impair the essential functions of RPE cells, including autophagy, lysosomal function, and energy metabolism.
“Dysfunctional FH, including the p.Y402H variant, can also lead to overactivation of the complement system, which can impair the essential functions of RPE cells, including autophagy, lysosomal function, and energy metabolism.”
From Bruch’s Membrane: A Key Consideration with Complement-Based Therapies for Age-Related Macular Degeneration (2023) · cites this paper as [136]
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- Authors
- Hallam, D., Collin, J., Bojic, S., Chichagova, V., Buskin, A., Xu, Y., Lafage, L., Otten, E. G., Anyfantis, G., Mellough, C., Przyborski, S., Alharthi, S., Korolchuk, V., Lotery, A., Saretzki, G., McKibbin, M., Armstrong, L., Steel, D., Kavanagh, D., & Lako, M.
- Affiliations
- Centre for Life (GB)
- a Institute of Genetic Medicine, International Centre for Life, United Kingdom
- Newcastle University (GB)
- Durham University (GB)
- King Abdulaziz University (SA)
- University of Southampton (GB)
- Leeds Teaching Hospitals NHS Trust (GB)
- Corresponding author
- Lako, Majlinda
- ORCID
- Venue
- Stem Cells
- Publisher
- Oxford University Press (OUP)
- Published
- 2017-10-09
- Volume
- 35
- Issue
- 11
- Pages
- 2305-2320
- ISSN
- 1066-5099 (ISSN-L)
- 1549-4918
- PMC
- PMC5698780
- OpenAlex
- W2784771549
- Cited by
- 75
- References
- 64
- Citations by year
- 2026: 6 · 2025: 4 · 2024: 9 · 2023: 7 · 2022: 13 · 2021: 15 · 2020: 6 · 2019: 8 · 2018: 7
- FWCI
- 5.60
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Stem Cells (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- ePrints Soton (University of Southampton) (acceptedVersion)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
- Durham Research Online (Durham University) (acceptedVersion, other-oa)
- Durham Research Online (Durham University) (submittedVersion, cc-by)
- Newcastle University ePrints (Newcastle Univesity) (cc-by)
- Funders
- Macular Society U.K.
- FP7 Ideas, European Research Council (614620)
- Biotechnology and Biological Sciences Research Council (BB/I020209/1)
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Keywords
- age-related macular degeneration, complement factor H, induced pluripotent stem cells, retinal pigment epithelium, complement activation, UV exposure, autophagy, lipid droplets, inflammation, patient-specific disease models
- MeSH terms
- Aged, Animals, Humans, Macular Degeneration, Ultraviolet Rays, Ultraviolet Therapy, Mice, SCID, Complement Factor H, Mice, Induced Pluripotent Stem Cells
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