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Ruchira Singh, Chad Galloway, leslie macdonald, Celia Soto, Danielle Benoit; Delineating the role of local vs. systemic influences in AMD and related macular dystrophies: An hiPSC approach.. Invest. Ophthalmol. Vis. Sci. 2018;59(9):4585.
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© ARVO (1962-2015); The Authors (2016-present)
The retinal pigment epithelium (RPE), choroidal endothelial cells and systemic factors have all been implicated in the development of drusen and choroidal neovascularizaton (CNV) in age related macular degeneration (AMD) and related macular dystrophies (MDs). Using patient-derived human induced pluripotent stem cells (hiPSCs), we have previously demonstrated that RPE dysfunction alone is sufficient for drusen biogenesis in multiple maculopathies. The purpose of this study was to utilize hiPSC-based disease modeling to determine the role of RPE vs. endothelial cells (ECs) vs. systemic influence (i.e. serum) in CNV development in AMD/MDs
hiPSC-RPE, hiPSC-ECs and serum were derived from AMD/MD patients as well as unaffected controls. Control and patient-derived hiPSC-ECs were encapsulated in degradable poly(ethylene glycol) (PEG) hydrogels to form CD31 and vWF positive vascular networks. In a subset of experiments, PEG-encapsulated hiPSC-ECs and subsequently hiPSC- vascular networks were exposed to 1) RPE conditioned media and/or 2) serum obtained from control vs. AMD/MD subjects. Endpoints used to assess pro-angiogenic properties included; endothelial cell proliferation, migration and invasion as well as vascular network tube formation, branching and long-term stability (up to 8 weeks) using published protocols.
Compared to the routine culture media and in contrast to control serum, control hiPSC-RPE conditioned media and/or serum positively influenced hiPSC-EC proliferation, migration/invasion and/or stability, tube formation and branching of the EC-derived vascular networks. In addition, patient-derived hiPSC-RPE conditioned media, hiPSC-ECs, and/or serum supplementation further increased 1) hiPSC-EC proliferation, migration/invasion and 2) spreading and branching of EC-derived vascular networks. Importantly, consistent with the role of RPE-secreted pro-angiogenic factors (VEGF, FGF2) in CNV, depletion of VEGF and/or FGF2 from patient-derived hiPSC-RPE conditioned media affected specific EC/vascular characteristics, including invasion.
The 3D hiPSC-derived vascular network model described here 1) demonstrates the ability of an hiPSC-derived cellular model to recapitulate known RPE-vascular interaction and 2) differentiates the role of local (RPE, EC) and systemic (serum) factors in modulating CNV-relevant vascular network properties in AMD/MDs.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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