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.
Highlights
Müller cells (MCs) are the major type of glial cells in the retina [1]
At a fixed frequency of 20 pulls per second (PPS) and 100 μA current amplitude, we noted that ramp waveforms significantly improved MC proliferation by nearly 2-fold compared to the non-stimulated control group and the sinusoidal or rectangular waveform (p < 0.005, paired t-test) (Figure 2B)
There was no significant differences among the peak values of MC proliferation under the optimal electrical stimulation (ES) condition in all experimental groups (Figure 2B–D). These results indicate that ES at 20 PPS, 100–300 μA, and a ramp waveform has the potential to significantly enhance MC proliferation in vitro
Summary
Müller cells (MCs) are the major type of glial cells in the retina [1] They extend from the inner limiting membrane (ILM) to the outer limiting membrane (OLM) and play a crucial role in maintaining retinal homeostasis. Our recent study reported potential reprogramming responses of MCs following ES in a mouse model of inherited photoreceptor degeneration [4]. In line with this observation, many years ago Chow and team accidently discovered that low electric current could reverse the visual field and function loss in a safety assessment of an artificial silicon retina microchip in retinitis pigmentosa (RP) patients, in which the effect was observed far from the initial stimulation point [5]. The use of electricity in medicine is not unperceivable [6], as it is widely used in cardiology, neurology, and psychiatry, gradually emerging in orthopedics and regenerative medicine as better and faster healing of wounds and bones [7,8,9,10,11,12]
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