期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 114, 期 39, 页码 E8214-E8223出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1710430114
关键词
human induced pluripotent stem cells; retinal pigment epithelium; macular dystrophies; drusen; sub-RPE deposits
资金
- BrightFocus Foundation
- David Bryant Trust
- Foundation Fighting Blindness
- Knights Templar Eye Foundation
- Research to Prevent Blindness
- Retina Research Foundation
- University of Rochester University Research Award
- Retina Research Foundation E.A. Humble Directorship of the McPherson Eye Research Institute
- Sandra Lemke Trout Chair in Eye Research
- NIH [EY013048]
- Australian Research Council [FT140100047]
- National Health and Medical Research Council (NHMRC) [1059369]
- NHMRC Practitioner Fellowship [1103329]
- NHMRC Elizabeth Blackburn Fellowship [1103013]
- Ophthalmic Research Institute of Australia
- Retina Australia
- Clinical and Translational Science Institute Grant [UL1TR000042]
- National Health and Medical Research Council of Australia [1059369, 1103329, 1103013] Funding Source: NHMRC
- Australian Research Council [FT140100047] Funding Source: Australian Research Council
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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