Transplantation of Human Induced Pluripotent Stem Cell-Derived Retinal Pigment Epithelium in a Swine Model of Geographic Atrophy.

Anna Duarri,Marc Biarnés,Elisabeth Izquierdo,Gema Martínez-Navarrete,Miriam García,Begoña Aran,Ángel Raya,Eduardo Rodríguez-Bocanegra,Lucía Lee Ferraro,Ricardo P Casaroli-Marano,Bernd Kuebler,Jordi Monés,Eduardo Fernandez,Anna Veiga,Esteve Trias,Eli Aguilera-Xiol

doi:10.3390/ijms221910497

Abstract

Background: The aim of this study was to test the feasibility and safety of subretinal transplantation of human induced pluripotent stem cell (hiPSC)-derived retinal pigment epithelium (RPE) cells into the healthy margins and within areas of degenerative retina in a swine model of geographic atrophy (GA). Methods: Well-delimited selective outer retinal damage was induced by subretinal injection of NaIO3 into one eye in minipigs (n = 10). Thirty days later, a suspension of hiPSC-derived RPE cells expressing green fluorescent protein was injected into the subretinal space, into the healthy margins, and within areas of degenerative retina. In vivo follow-up was performed by multimodal imaging. Post-mortem retinas were analyzed by immunohistochemistry and histology. Results: In vitro differentiated hiPSC-RPE cells showed a typical epithelial morphology, expressed RPE-related genes, and had phagocytic ability. Engrafted hiPSC-RPE cells were detected in 60% of the eyes, forming mature epithelium in healthy retina extending towards the border of the atrophy. Histological analysis revealed RPE interaction with host photoreceptors in the healthy retina. Engrafted cells in the atrophic zone were found in a patchy distribution but failed to form an epithelial-like layer. Conclusions: These results might support the use of hiPSC-RPE cells to treat atrophic GA by providing a housekeeping function to aid the overwhelmed remnant RPE, which might improve its survival and therefore slow down the progression of GA.

Highlights

Age-related macular degeneration (AMD) is the most common cause of blindness in people older than 50 years in industrialized countries, and affects between 14.9 and21.5 million people in Europe alone [1]
To assess the purity of hRPE-green fluorescent protein (GFP) cells, the human induced pluripotent stem cell (hiPSC) line together with hRPE-GFP derived from it were tested in parallel for Tra-1-60, a pluripotency marker, and for CD140b and CD59, retinal pigment epithelium (RPE)-specific markers, by flow cytometry (Figure 1B; Supplementary Figure S2). hRPE-GFP cells expressed
We showed here that hiPSC-RPE cells have the capacity to phagocytize photoreceptor outer segments (POS) in vitro

Summary

Introduction

Age-related macular degeneration (AMD) is the most common cause of blindness in people older than 50 years in industrialized countries, and affects between 14.9 and21.5 million people in Europe alone [1]. AMD is a degenerative, chronic, and progressive disease involving the retinal pigment epithelium (RPE) and choroid, which trigger the degeneration of the outer retina in the macula region of the eye [2]. Late-stage dry AMD can manifest as geographic atrophy (GA), which affects the macular region of the retina, causing progressive and irreversible loss of central vision due to the degeneration of retinal pigment epithelium (RPE) and photoreceptor cells, and accounts for 80% of all cases. The aim of this study was to test the feasibility and safety of subretinal transplantation of human induced pluripotent stem cell (hiPSC)-derived retinal pigment epithelium (RPE) cells into the healthy margins and within areas of degenerative retina in a swine model of geographic atrophy (GA). Conclusions: These results might support the use of hiPSC-RPE cells to treat atrophic GA by providing a housekeeping function to aid the overwhelmed remnant RPE, which might improve its survival and slow down the progression of GA

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Methods

Results

Conclusion