Electrical Stimulation Induces Retinal Müller Cell Proliferation and Their Progenitor Cell Potential

Abstract

Non-invasive electrical stimulation (ES) is increasingly applied to improve vision in untreatable eye conditions, such as retinitis pigmentosa and age-related macular degeneration. Our previous study suggested that ES promoted retinal function and the proliferation of progenitor-like glial cells in mice with inherited photoreceptor degeneration; however, the underlying mechanism remains obscure. Müller cells (MCs) are thought to be dormant residential progenitor cells that possess a high potential for retinal neuron repair and functional plasticity. Here, we showed that ES with a ramp waveform of 20 Hz and 300 µA of current was effective at inducing mouse MC proliferation and enhancing their expression of progenitor cell markers, such as <i>Crx</i> (cone-rod homeobox) and <i>Wnt7</i>, as well as their production of trophic factors, including ciliary neurotrophic factor. RNA sequencing revealed that calcium signaling pathway activation was a key event, with a false discovery rate of 5.33 × 10^-8 (<i>p</i> = 1.78 × 10^-10) in ES-mediated gene profiling changes. Moreover, the calcium channel blocker, nifedipine, abolished the observed effects of ES on MC proliferation and progenitor cell gene induction, supporting a central role of ES-induced Ca²⁺ signaling in the MC changes. Our results suggest that low-current ES may present a convenient tool for manipulating MC behavior toward neuroregeneration and repair.