IPSC-Derived Retinal Pigment Epithelium Allografts Do Not Elicit Detrimental Effects in Rats: A Follow-Up Study.

Peter D Westenskow,Felicitas Bucher,Stephen Bravo,Jonathan H Lin,Edith Aguilar,Liliana P Paris,Martin Friedlander,Daniel Feitelberg,Toshihide Kurihara

doi:10.1155/2016/8470263

Abstract

Phototransduction is accomplished in the retina by photoreceptor neurons and retinal pigment epithelium (RPE) cells. Photoreceptors rely heavily on the RPE, and death or dysfunction of RPE is characteristic of age-related macular degeneration (AMD), a very common neurodegenerative disease for which no cure exists. RPE replacement is a promising therapeutic intervention for AMD, and large numbers of RPE cells can be generated from pluripotent stem cells. However, questions persist regarding iPSC-derived RPE (iPS-RPE) viability, immunogenicity, and tumorigenesis potential. We showed previously that iPS-RPE prevent photoreceptor atrophy in dystrophic rats up until 24 weeks after implantation. In this follow-up study, we longitudinally monitored the same implanted iPS-RPE, in the same animals. We observed no gross abnormalities in the eyes, livers, spleens, brains, and blood in aging rats with iPSC-RPE grafts. iPS-RPE cells that integrated into the subretinal space outlived the photoreceptors and survived for as long as 2 1/2 years while nonintegrating RPE cells were ingested by host macrophages. Both populations could be distinguished using immunohistochemistry and electron microscopy. iPSC-RPE could be isolated from the grafts and maintained in culture; these cells also phagocytosed isolated photoreceptor outer segments. We conclude that iPS-RPE grafts remain viable and do not induce any obvious associated pathological changes.

Highlights

The diverse functions of retinal pigment epithelium (RPE) cells are essential for photoreceptor activity [1]
Other groups and ours have characterized SC-RPE using multiple methods. These studies have shown that SC-RPE strongly resemble primary RPE based on morphological, functional, transcriptomic, proteomic, and metabolomic analyses, and, most importantly, they function in vivo to significantly slow retinal degeneration [4, 6,7,8, 11, 14, 19,20,21,22,23,24]
There were no significant differences between the weights of the uninjected, PBS injected, or induced pluripotent stem cells (iPSCs)-derived RPE (iPS-RPE) injected Royal College of Surgeons (RCS) rats

Summary

Introduction

The diverse functions of retinal pigment epithelium (RPE) cells are essential for photoreceptor activity [1]. Other groups and ours have characterized SC-RPE using multiple methods These studies have shown that SC-RPE strongly resemble primary RPE based on morphological, functional, transcriptomic, proteomic, and metabolomic analyses, and, most importantly, they function in vivo to significantly slow retinal degeneration [4, 6,7,8, 11, 14, 19,20,21,22,23,24]. Evidence from preclinical and early phase clinical trials has shown no adverse ocular effects in rodents or patients with hiPS-RPE

Methods

Results

Conclusion