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 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.

Neuroprotective Effects and Therapeutic Potential of Transcorneal Electrical Stimulation for Depression

“…Concordantly, TES positively modulated the expression of the brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF) in the retina, which prolonged the survival of photoreceptors and preserved retinal functions in mouse models of photoreceptor degeneration induced by light or N-methyl-N-nitrosourea [ 36 , 46 ]. Studies using Müller cell cultures also demonstrated that TES could stimulate the production of IGF-1, BDNF, and CNTF, resulting in significant induction of Müller cell proliferation [ 37 , 38 , 39 , 40 ]. The induction of these growth factors by electrical stimulation was suggested to be dependent on the activation of L-type voltage-dependent calcium channels (L-VDCCs), as blocking L-VDCCs downregulated IGF-1 and BDNF, as well as attenuating Müller cell proliferation [ 37 , 38 , 40 ].…”

“…Studies using Müller cell cultures also demonstrated that TES could stimulate the production of IGF-1, BDNF, and CNTF, resulting in significant induction of Müller cell proliferation [ 37 , 38 , 39 , 40 ]. The induction of these growth factors by electrical stimulation was suggested to be dependent on the activation of L-type voltage-dependent calcium channels (L-VDCCs), as blocking L-VDCCs downregulated IGF-1 and BDNF, as well as attenuating Müller cell proliferation [ 37 , 38 , 40 ].…”

“…Although the modulation effects of TES in these non-visual brain regions have yet to be confirmed, both PFC and PHG are involved in mood alterations [ 32 ], suggesting that TES may have a role in regulating emotion. The potential neuroprotective properties of TES are possibly achieved through regulating neuroplasticity [ 30 , 33 ], neurotrophic expression [ 34 , 35 , 36 , 37 , 38 , 39 , 40 ], inflammatory responses [ 39 , 41 , 42 , 43 , 44 ], apoptosis [ 36 , 45 , 46 , 47 ], glutamate metabolism [ 48 ], and retinal blood flow [ 49 , 50 ]. The putative neuroprotective effects of TES on mood control are further supported by its shared mechanisms of action with current antidepressant treatments, including its neuroprotective effects against apoptosis and inflammation, as well as its ability to promote neurotrophic expression.…”

Bioelectric Potential in Next-Generation Organoids: Electrical Stimulation to Enhance 3D Structures of the Central Nervous System

“…The human retina differs significantly from that of lower order animals, and human PSC-derived organoids therefore provide a better platform to study EF-induced therapeutic effects on the human retina. In vitro , primary eye-derived retinal glial cells (Müller Glia) were found to respond to electrical stimulation with increased proliferation and expression of cell fate determinant genes ( Enayati et al, 2020 ). Specifically, this was linked to the action of Calcium signalling ( Enayati et al, 2020 ).…”

“…In vitro , primary eye-derived retinal glial cells (Müller Glia) were found to respond to electrical stimulation with increased proliferation and expression of cell fate determinant genes ( Enayati et al, 2020 ). Specifically, this was linked to the action of Calcium signalling ( Enayati et al, 2020 ). Several studies have also reported a regenerative response of the output neurons of the retina, the retinal ganglion cells, in response to biomimetic stimulation ( Fu et al, 2015 ; Gordon, 2016 ).…”