Transplanted pluripotent stem cell-derived photoreceptor precursors elicit conventional and unusual light responses in mice with advanced retinal degeneration.

Darin Zerti,Majlinda Lako,Evelyne Sernagor,Lyle Armstrong,Birthe Dorgau,Joseph Collin,Marius Ader,Gerrit Hilgen

doi:10.1002/stem.3365

Abstract

Retinal dystrophies often lead to blindness. Developing therapeutic interventions to restore vision is therefore of paramount importance. Here we demonstrate the ability of pluripotent stem cell-derived cone precursors to engraft and restore light responses in the Pde6brd1 mouse, an end-stage photoreceptor degeneration model. Our data show that up to 1.5% of precursors integrate into the host retina, differentiate into cones, and engraft in close apposition to the host bipolar cells. Half of the transplanted mice exhibited visual behavior and of these 33% showed binocular light sensitivity. The majority of retinal ganglion cells exhibited contrast-sensitive ON, OFF or ON-OFF light responses and even motion sensitivity; however, quite a few exhibited unusual responses (eg, light-induced suppression), presumably reflecting remodeling of the neural retina. Our data indicate that despite relatively low engraftment yield, pluripotent stem cell-derived cone precursors can elicit light responsiveness even at advanced degeneration stages. Further work is needed to improve engraftment yield and counteract retinal remodeling to achieve useful clinical applications.

Highlights

Genetic defects in rods, cones or in the retinal pigment epithelium trigger the loss of the sensory retina, effectively leaving the neuralDarin Zerti and Gerrit Hilgen contributed to this study.retina deafferented
We have developed robust protocols for generation of photoreceptors within pluripotent stem cell derived retinal organoids[19,21,25] and have shown that these are able to engraft into animal models of retinal degeneration.[35]
We investigated the ability of transplanted human embryonic stem cells (hESCs)-derived cone precursors to elicit light responses in adult retinal ganglion cell (RGC) in the Pde6brd[1] mouse, characterized by advanced retinal degeneration

Summary

| INTRODUCTION

Cones or in the retinal pigment epithelium trigger the loss of the sensory retina, effectively leaving the neural. The latter responds to this challenge by profound remodeling of the surviving cells and connectivity,[1,2] posing an enormous challenge to successful potential therapies based on genetic, cellular, and bionic approaches. These changes have been extensively described in animal models such as the Pde6brd[1] mouse, a model of autosomal recessive form of Retinitis Pigmentosa.[3,4]. We demonstrate the ability of transplanted photoreceptors to successfully restore light-responses in RGCs in Pde6brd[1] retinas with end-stage degeneration

Significance statement

| RESULTS

| DISCUSSION

Findings

| MATERIALS AND METHODS

| CONCLUSION