In late stages of inherited and acquired retinal diseases such as Stargardt disease (STGD) or dry age-related macular degeneration (AMD), loss of retinal pigment epithelia (RPE) cells and subsequently photoreceptors in the macular area result in a dramatic decline of central visual function. Repopulating this area with functional RPE cells may prevent or decline the progression of photoreceptor loss. In the present study, the viability, survival, and integration of human induced pluripotent stem cell (hiPSC)-derived RPE cells (hiPSC-RPE) is assessed generated using clinical-grade protocol and cultured on a clinically relevant scaffold (poly-L-lactide-co-D, L-lactide, PDLLA) after subretinal implantation in immunosuppressed minipigs for up to 6 weeks. It is shown that transplanted hiPSC-RPE cells maintain the RPE cell features such as cell polarity, hexagonal shape, and cell-cell contacts, and interact closely with photoreceptor outer segments without signs of gliosis or neuroinflammation throughout the entire period of examination. In addition, an efficient immunosuppressing strategy with a continuous supply of tacrolimus is applied. Continuous verification and improvement of existing protocols are crucial for its translation to the clinic. The results support the use of hiPSC-RPE on PDLLA scaffold as a cell replacement therapeutic approach for RPE degenerative diseases.

3rd Faculty of Medicine Charles University Prague Vinohrady Teaching Hospital Department of Ophthalmology Prague 10034 Czech Republic

Department of Cell Biology Faculty of Science Charles University Prague 12800 Czech Republic

Department of Ophthalmology Center for Eye Research Oslo University Hospital and University of Oslo Oslo 0192 Norway

Department of Ophthalmology Faculty of Medicine University of Szeged Szeged 6720 Hungary

Department of Ophthalmology Justus Liebig University Giessen 35390 Giessen Germany

Institute of Animal Physiology and Genetics Czech Academy of Sciences Libechov 27721 Czech Republic

Institute of Experimental Medicine Czech Academy of Sciences Department of Neuroregeneration Prague 14220 Czech Republic

Institute of Macromolecular Chemistry Czech Academy of Sciences Prague 16200 Czech Republic

Ocular and Stem Cell Translational Research Section National Eye Institute NIH Bethesda MD 20892 USA

Retinal degeneration Lab Department of Animal Production and Health Public Veterinary Health and Food Science and Technology School of Veterinary Medicine Universidad Cardenal Herrera CEU CEU Universities Alfara del Patriarca 46115 Spain

Stem Cell Therapies in Neurodegenerative Diseases Lab Centro de Investigación Príncipe Felipe Valencia 46012 Spain

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