Function of human pluripotent stem cell-derived photoreceptor progenitors in blind mice.

Alona O Barnea-Cramer,Shi-Jiang Lu,Chenmei Luo,Mandeep S Singh,Michelle E Mcclements,Robert E Maclaren,Wei Wang,Robert Lanza,Hongguang Huo,Alun R Barnard

doi:10.1038/srep29784

Abstract

Photoreceptor degeneration due to retinitis pigmentosa (RP) is a primary cause of inherited retinal blindness. Photoreceptor cell-replacement may hold the potential for repair in a completely degenerate retina by reinstating light sensitive cells to form connections that relay information to downstream retinal layers. This study assessed the therapeutic potential of photoreceptor progenitors derived from human embryonic and induced pluripotent stem cells (ESCs and iPSCs) using a protocol that is suitable for future clinical trials. ESCs and iPSCs were cultured in four specific stages under defined conditions, resulting in generation of a near-homogeneous population of photoreceptor-like progenitors. Following transplantation into mice with end-stage retinal degeneration, these cells differentiated into photoreceptors and formed a cell layer connected with host retinal neurons. Visual function was partially restored in treated animals, as evidenced by two visual behavioral tests. Furthermore, the magnitude of functional improvement was positively correlated with the number of engrafted cells. Similar efficacy was observed using either ESCs or iPSCs as source material. These data validate the potential of human pluripotent stem cells for photoreceptor replacement therapies aimed at photoreceptor regeneration in retinal disease.

Highlights

Photoreceptor degeneration due to retinitis pigmentosa (RP) is a primary cause of inherited retinal blindness
After 10 days of in vitro cell differentiation, more than 90% of cells expressed paired box 6 (PAX6), nestin and sex determining region Y-box 2 (SOX2) (Supplementary Fig. S2c,d), suggesting they were committed to neural stem cells
Real-time quantitative reverse transcription polymerase chain reaction demonstrated a dramatic decrease in the expression of octamer-binding transcription factor 4 (OCT4) and nanog, two critical pluripotent genes (Supplementary Fig. S3c). These results demonstrated a robust differentiation of Human embryonic stem cell (hESC) towards retinal neural cells with gene profiles corresponding to eye field progenitors (EFP)

Summary

Introduction

Photoreceptor degeneration due to retinitis pigmentosa (RP) is a primary cause of inherited retinal blindness. This study assessed the therapeutic potential of photoreceptor progenitors derived from human embryonic and induced pluripotent stem cells (ESCs and iPSCs) using a protocol that is suitable for future clinical trials. Similar efficacy was observed using either ESCs or iPSCs as source material These data validate the potential of human pluripotent stem cells for photoreceptor replacement therapies aimed at photoreceptor regeneration in retinal disease. Rod and cone photoreceptors, which comprise the retinal outer nuclear layer (ONL), are the light sensing cells of the eye. They convert light signals into electrical impulses, initiating the visual transduction cascade which sends visual information to the brain. Medium- to long-term safety, graft survival, and possible biological activity of hESC-RPE in www.nature.com/scientificreports/

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