Electrical Stimulation of Schwann Cells Promotes Sustained Increases in Neurite Outgrowth

Abstract

Endogenous electric fields are instructive during embryogenesis by acting to direct cell migration, and postnatally, they can promote axonal growth after injury (McCaig 1991, Al-Majed 2000. However, the mechanisms for these changes are not well understood. Application of an appropriate electrical stimulus may increase the rate and success of nerve repair by directly promoting axonal growth. Previously, DC electrical stimulation at 50 mV/mm (1 mA, 8 h duration) was shown to promote neurite outgrowth and a more pronounced effect was observed if both peripheral glia (Schwann cells) and neurons were co-stimulated. If electrical stimulation is delivered to an injury site, both the neurons and all resident non-neuronal cells [e.g., Schwann cells, endothelial cells, fibroblasts] will be treated and this biophysical stimuli can influence axonal growth directly or indirectly via changes to the resident, non-neuronal cells. In this work, non-neuronal cells were electrically stimulated, and changes in morphology and neuro-supportive cells were evaluated. Schwann cell response (morphology and orientation) was examined after an 8 h stimulation over a range of DC fields (0-200 mV/mm, DC 1 mA), and changes in orientation were observed. Electrically prestimulating Schwann cells (50 mV/mm) promoted 30% more neurite outgrowth relative to co-stimulating both Schwann cells with neurons, suggesting that electrical stimulation modifies Schwann cell phenotype. Conditioned medium from the electrically prestimulated Schwann cells promoted a 20% increase in total neurite outgrowth and was sustained for 72 h poststimulation. An 11-fold increase in nerve growth factor but not brain-derived neurotrophic factor or glial-derived growth factor was found in the electrically prestimulated Schwann cell-conditioned medium. No significant changes in fibroblast or endothelial morphology and neuro-supportive behavior were observed poststimulation. Electrical stimulation is widely used in clinical settings; however, the rational application of this cue may directly impact and enhance neuro-supportive behavior, improving nerve repair.

Thermally drawn fibers as nerve guidance scaffolds

“…As PNS repair is highly dependent upon the supportive behavior of Schwann cells [43–45], understanding glial migration may provide insights into overcoming growth-inhibiting responses to nerve injury [35]. Since the topography of Schwann cells can influence the orientation of neurite outgrowth, we investigated the migration of these cells within the fiber scaffolds.…”

“…Since thermal drawing was previously applied to integrate optical waveguides, electrodes, and microfluidic channels into neural fiber probes [29, 30], it may enable future incorporation of electrical [43, 54] or optical stimulation [32] means for accelerated nerve regeneration without sacrificing the valuable regenerative space.…”

Peripheral Nerve Regeneration Strategies: Electrically Stimulating Polymer Based Nerve Growth Conduits

“…75–77 In addition, neural progenitors resulted in neurite outgrowth following ES. 151 The use of Schwann cells without ES in the regeneration of long nerve defects has been reported to be positive 152 in some cases and non-beneficial in others. 153 However, the use of ES in conjunction with Schwann cells may produce positive effects in terms of nerve regeneration.…”

Silk–tropoelastin protein films for nerve guidance

“…Schwann cells play a significant role in nerve regeneration through several mechanisms including production of neurotrophic factors (52, 53) and myelination of the regenerating axons (54). Furthermore, increased Schwann cell migration/presence at regenerating site has been shown to increase the efficacy of peripheral nerve repair in in vivo studies (23).…”