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

Cells. 2020 Mar 23;9(3):781. doi: 10.3390/cells9030781.

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 Crx (cone-rod homeobox) and Wnt7, 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 (p = 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.

Keywords: Müller cells; electrical-stimulation; glial cells; proliferation; retina; retinitis pigmentosa.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium Channels, L-Type / metabolism
  • Calcium Signaling
  • Cell Differentiation
  • Cell Proliferation
  • Cells, Cultured
  • Electric Stimulation
  • Ependymoglial Cells / cytology*
  • Gene Expression Regulation
  • Mice, Inbred C57BL
  • Stem Cells / cytology*
  • Transcription Factors / metabolism
  • Up-Regulation

Substances

  • Calcium Channels, L-Type
  • Transcription Factors