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A Human Retinal Pigment Epithelium-Based Screening Platform Reveals Inducers of Photoreceptor Outer Segments Phagocytosis.

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Barsacchi,  Rico
Max Planck Institute for Molecular Cell Biology and Genetics, Max Planck Society;

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Bickle,  Marc
Max Planck Institute for Molecular Cell Biology and Genetics, Max Planck Society;

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Tanaka,  Elly M.
Max Planck Institute for Molecular Cell Biology and Genetics, Max Planck Society;

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Citation

Schreiter, S., Vafia, K., Barsacchi, R., Tsang, S. H., Bickle, M., Ader, M., et al. (2020). A Human Retinal Pigment Epithelium-Based Screening Platform Reveals Inducers of Photoreceptor Outer Segments Phagocytosis. Stem cell reports, 15(6), 1347-1361. doi:10.1016/j.stemcr.2020.10.013.


Cite as: https://hdl.handle.net/21.11116/0000-0008-A242-6
Abstract
Phagocytosis is a key function in various cells throughout the body. A deficiency in photoreceptor outer segment (POS) phagocytosis by the retinal pigment epithelium (RPE) causes vision loss in inherited retinal diseases and possibly age-related macular degeneration. To date, there are no effective therapies available aiming at recovering the lost phagocytosis function. Here, we developed a high-throughput screening assay based on RPE derived from human embryonic stem cells (hRPE) to reveal enhancers of POS phagocytosis. One of the hits, ramoplanin (RM), reproducibly enhanced POS phagocytosis and ensheathment in hRPE, and enhanced the expression of proteins known to regulate membrane dynamics and ensheathment in other cell systems. Additionally, RM rescued POS internalization defect in Mer receptor tyrosine kinase (MERTK) mutant hRPE, derived from retinitis pigmentosa patient induced pluripotent stem cells. Our platform, including a primary phenotypic screening phagocytosis assay together with orthogonal assays, establishes a basis for RPE-based therapy discovery aiming at a broad patient spectrum.