Developing 3D patient-specific iPS cell derived RPE/choroid models

National Eye Institute

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Abstract

Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly and progresses to two advanced stages: dry and wet AMD. The dry form is triggered by the loss of retinal pigment epithelium (RPE) cells, followed by photoreceptor (PR) degeneration and thinning of the choroid. In contrast, the wet form is characterized by abnormal proliferation of choroidal blood vessels. Both disease pathways are believed to originate at the PR/RPE/choroid interface at the back of the eye. However, because of the lack of physiologically relevant human models, the early events that initiate disease and drive structural and functional changes in this complex remain poorly understood. To address this gap, we combined bioprinting, tissue engineering, and induced pluripotent stem (iPSC) technology to create a 3D in vitro model of the RPE–choroid unit. Using a collagen-based gel, we encapsulated patient-derived iPSC endothelial cells, choroidal fibroblasts, and pericytes, and bioprinted them to form a microvascular network on one side of a biodegradable scaffold. On the opposite side, we cultured a monolayer of RPE cells differentiated from the same patient’s iPSCs. This engineered 3D tissue recapitulates both the anatomy and functional properties of the native RPE–choroid complex. Importantly, the vascular network responds to VEGF by proliferating—closely mimicking the pathological hallmark of wet AMD. This platform enables the discovery of early disease pathways and provides an experimental system for testing candidate therapeutics for wet AMD. In follow-up studies, we are investigating how macrophages and fibroblasts contribute to the development and pathology of this engineered tissue. By incorporating macrophages into the choroid compartment, we are now studying their role in vascular regulation and AMD progression.