American Society for Peripheral Nerve
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Conditioning electrical stimulation promotes nerve regeneration in a non-injurious and non-inflammatory manner
Jenna-Lynn Senger, MD PhD FRCSC1; Leah Acton, BSc2; Paige Hardy, BSc.1; Ming Chan, MB ChB, FRCPC3; Christine A Webber, MD
1University of Alberta, Edmonton, AB, Canada; 2Univeristy of Alberta, Edmonton, AB, Canada; 3Plastic and Reconstructive Surgery, University of Alberta, Edmonton, AB, Canada

Due to the slow rate of regeneration (1-3mm/day), nerve repair surgeries following proximal peripheral nerve injury are often incomplete. Despite the advancements in surgical techniques, over half of patients with peripheral nerve injury experience lifelong deficits that can severely impact quality of life. The conditioning crush lesion (CCL), a technique in which a crush injury is performed one week prior to a nerve transection and repair surgery, increases the rate of nerve growth 2-4-fold. However, CCL cannot be translated to clinical use as it requires an intentional nerve injury which evokes an invasive inflammatory response. Conditioning electrical stimulation (CES) upregulates the same regeneration-associated genes (RAGs) as CCL to accelerate nerve regeneration and promote sensorimotor functional recovery. We hypothesized that unlike CLL, CES is non-injurious and non-inflammatory. One day post conditioning, there was an upregulation of activation transcription factor-3 expression (ATF3) in the CCL, but not the CES dorsal root ganglion (DRG) neurons. Lineage tracing studies of CX3CR1-expressing tissue-resident macrophages (TdTom+; Iba-1+) demonstrated an infiltration of monocyte-derived macrophages at the DRG and nerve (TdTom-; Iba-1+) 3-7 days following CCL. There was no increase in tissue resident macrophage expression (TdTom+; Iba-1+) at the DRG or nerve following CCL. In contrast, CES did not increase monocyte-derived n or tissue resident macrophages density within the nerve or DRG. Further, innate macrophages expression at the DRG and nerve did not increase their activation (as depicted by dectin-1 and IBA-1 expression) following CES. Ablation of the CX3CR1 population of macrophages (monocyte-derived and tissue resident macrophages) demonstrated that the effects of CCL, but not CES, were reduced suggesting different mechanism of action from immune cells in these two conditioning events. In summary, unlike CCL which requires nerve injury that is associated with monocyte-derived macrophage entry into the DRG to evoke a pro-regenerative effect, CES activates RAG expression and accelerates nerve regeneration in a manner independent of nerve injury macrophage accumulation. Single nuclear RNA-sequencing will be pursued to determine the mechanism through which CES promotes nerve regeneration.


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