Bioelectric Modulation to Enhance Pluripotent Stem Cell-Derived Photoreceptor Cell Therapy

Abstract

Retinal degeneration, leading to loss of light-sensing photoreceptor cells, is the leading cause of blindness worldwide. Photoreceptor cell replacement therapy offers a universal approach to treat incurable blindness. Human pluripotent stem cell-derived retinal organoids model the in vivo retina and offer a renewable source of transplantable photoreceptors. This project sought to improve cell therapy efficacy via bioelectric modulation. Electrical stimulation (ES) is an emerging technique implicated in neuroprotection and developmental cell processes. The investigations herein aimed to test the hypothesis that 1) bioelectric modulation of retinal organoids enhances development and differentiation of retinal organoids, 2) ES offers neuroprotection for retinal degeneration in vivo, and 3) improves transplanted cell integration and visual rescue in a mouse model of severe retinal degeneration. We implemented ES to retinal organoid differentiation and characterised effects on differentiation and photoreceptor populations at the cellular and molecular level. We also tested bioelectric modulation on the diseased retina in vivo. Non-invasive transcorneal ES revealed changes in tissue structure, gene expression and propensity to protect visual function. Finally, by combining ES with photoreceptor cell transplantation in vivo, we examined the morphological and functional behaviour of transplanted cells and degenerate retina in response to the bioelectric modulation.

These studies demonstrated a significant capacity for ES to enhance retinal organoid cultures and promote photoreceptor differentiation. In vivo ES offered neuroprotective effects to retinas undergoing severe retinal degeneration confirming the potential of this approach to slow down disease progression. When combined with photoreceptor transplantation, ES improved transplant outcome. Together these results promise significant impacts in accelerating efficacious treatments for blindness to clinics.