Drusen in patient-derived hiPSC-RPE models of macular dystrophies
Open accessAbstract
Age-related macular degeneration (AMD) and related macular dystrophies (MDs) are a major cause of vision loss. However, the mechanisms underlying their progression remain ill-defined. This is partly due to the lack of disease models recapitulating the human pathology. Furthermore, in vivo studies have yielded limited understanding of the role of specific cell types in the eye vs. systemic influences (e.g., serum) on the disease pathology. Here, we use human induced pluripotent stem cell-retinal pigment epithelium (hiPSC-RPE) derived from patients with three dominant MDs, Sorsby's fundus dystrophy (SFD), Doyne honeycomb retinal dystrophy/malattia Leventinese (DHRD), and autosomal dominant radial drusen (ADRD), and demonstrate that dysfunction of RPE cells alone is sufficient for the initiation of sub-RPE lipoproteinaceous deposit (drusen) formation and extracellular matrix (ECM) alteration in these diseases. Consistent with clinical studies, sub-RPE basal deposits were present beneath both control (unaffected) and patient hiPSC-RPE cells. Importantly basal deposits in patient hiPSC-RPE cultures were more abundant and displayed a lipid- and protein-rich "drusen-like" composition. Furthermore, increased accumulation of COL4 was observed in ECM isolated from control vs. patient hiPSC-RPE cultures. Interestingly, RPE-specific up-regulation in the expression of several complement genes was also seen in patient hiPSC-RPE cultures of all three MDs (SFD, DHRD, and ADRD). Finally, although serum exposure was not necessary for drusen formation, COL4 accumulation in ECM, and complement pathway gene alteration, it impacted the composition of drusen-like deposits in patient hiPSC-RPE cultures. Together, the drusen model(s) of MDs described here provide fundamental insights into the unique biology of maculopathies affecting the RPE-ECM interface.
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iPS-RPE from patients with different monogenic forms of macular degeneration accumulate drusen deposits after 90 days of culture.
“and iPS-RPE from patients with different monogenic forms of macular degeneration were observed to accumulate drusen deposits after 90 days of culture (Galloway et al., 2017).”
From The cell biology of the retinal pigment epithelium (2020) · cites this paper as Galloway et al., 2017
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- Authors
- Galloway, C. A., Dalvi, S., Hung, S. S. C., MacDonald, L. A., Latchney, L. R., Wong, R. C. B., Guymer, R. H., Mackey, D. A., Williams, D. S., Chung, M. M., Gamm, D. M., Pébay, A., Hewitt, A. W., & Singh, R.
- Affiliations
- University of Rochester Medicine (US)
- The University of Melbourne (AU)
- Lions Eye Institute (AU)
- University of California, Los Angeles (US)
- University of Wisconsin–Madison (US)
- University of Tasmania (AU)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2017-09-06
- Volume
- 114
- Issue
- 39
- Pages
- E8214-E8223
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC5625924
- OpenAlex
- W2750719761
- Cited by
- 123
- References
- 65
- Citations by year
- 2026: 11 · 2025: 8 · 2024: 18 · 2023: 11 · 2022: 20 · 2021: 18 · 2020: 13 · 2019: 14 · 2018: 10
- FWCI
- 9.87
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eCite Digital Repository (University of Tasmania) (submittedVersion)
- UTAS Research Repository (submittedVersion)
- UWA Profiles and Research Repository (UWA) (submittedVersion, other-oa)
- Figshare (submittedVersion, cc-by)
- Funders
- BrightFocus Foundation (M2015267)
- Foundation Fighting Blindness (TA-RM-0616-0702-UR)
- Research to Prevent Blindness (RPB-Singh, RPB-Feldon)
- Knights Templar Eye Foundation (KTEF-Singh)
- Retina Research Foundation (RRF-Singh)
- Australian Research Council (ARC-Pebay)
- The Ophthalmic Research Institute of Australia (ORIA-Hewitt)
- David Bryant Trust (DBT-Singh)
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Retinal Imaging and Analysis
- Keywords
- drusen, macular dystrophy, age-related macular degeneration, retinal pigment epithelium, Sorsby's fundus dystrophy, Malattia Leventinese, extracellular matrix, type IV collagen, complement pathway, serum exposure, disease modeling
- MeSH terms
- Blindness, Cells, Cultured, Humans, Macular Degeneration, Retinal Drusen, Optic Disk Drusen, Eye Diseases, Hereditary, Extracellular Matrix Proteins, Bruch Membrane, Tissue Inhibitor of Metalloproteinase-3, Collagen Type IV, Retinal Pigment Epithelium, Induced Pluripotent Stem Cells
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