Introduction: Age-related and inherited forms of retinal degenerations (RDs) are the leading cause of irreversible vision loss world-wide. Most forms of RDs lead to degeneration of the retinal pigment epithelium (RPE), the photoreceptor layer, and the choriocapillaris (CC). Especially in age-related macular degeneration (AMD), RPE atrophy initiates the death of photoreceptors and the loss of choroidal vasculature. Although the wet form of AMD has treatment options, dry AMD has no treatment available so far. It could be attributed to inadequate models and a lack of understanding of the disease initiating mechanism.
Methods: Human induced pluripotent stem cells (iPSCs) and complement factor H (CFH) gene compromised iPSC (CFH-KO-iPSC) were differentiated to endothelial cells, pericytes, fibroblasts, and RPE cells. For comparisons, primary retinal endothelial cells, choroidal pericytes, and choroidal fibroblasts were used. “Bioink” derived from cell-hydrogel mixture was bioprinted on the basal side of PLGA polymer. After 1 week of bioprinting, iPSC-derived RPE cells were seeded on the apical side of the scaffold and matured additional 4-5 weeks to form the outer blood-retinal barrier.
Results: In this 3D-RPE-CC tissue, a fully polarized RPE monolayer provides barrier resistance, induces CC fenestration, and supports the formation of Bruch’s-membrane-like structure (2-4 µm thick) by inducing changes in gene expression in cells of the choroid. Complement activation in the 3D-RPE-CC tissue triggers dry AMD phenotypes (including subRPE lipid-rich deposits called drusen and CC degeneration). HIF-α stabilization or STAT3 overactivation induces CC neovascularization and type-I wet AMD phenotype, which can be suppressed using anti-VEGF antibodies This provides clinical relevance of our tissue. Discussion and conclusion: Using patient-specific iPSCs we have determined differential roles of CFH in RPE and CC, providing a new tool for testing effects of CFH and complement pathway-targeting gene therapies. Our approach led to the development of physiologically relevant 3D models that faithfully recapitulate the disease phenotype and are being used to study disease mechanisms and discover new drugs and gene therapies.