American Society for Peripheral Nerve

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Macrophages Regulate Schwann Cell Maturation Following Nerve Injury
Rajiv Midha, MD, MSc, FRCS(C); Jo Stratton, PhD; Alexandra Holmes, BSc; Jeff Biernaskie, PhD
University of Calgary, Calgary, AB, Canada

Introduction
Many individuals are affected by nerve injury, resulting in functional deficits and pain. Pro-regenerative macrophages are well known for their role in promoting tissue repair and remodeling a process that is important for full functional recovery in many injury environments. However, the role of pro-regenerative macrophages in nerve injury is not as well defined. We aimed to decipher the role macrophage play during nerve regeneration.

Methods
First, we performed single cell RNAseq on macrophages from day 3 and 8 post-injury, discovering that these cells expressed an array of array of factors including Growth Arrest Specific 6 (Gas6), HBEGF and IL6. Following the addition of these factors to immature Schwann cell cultures, we found that Schwann cells were responsive to Gas6 and IL6, namely Schwann cells exited cell cycle, suggestive of a role for macrophages during the process of Schwann cell maturation. We performed nerve injury in Thy1-GFP reporter rats, and eight days later treated them with mannosylated clodronate liposomes to ablate macrophages, or control liposomes. We then assayed the rats for electrophysiology and myelination indices.

Results
Using compound muscle action potential analysis, we found that macrophage ablation resulted in long-term deficits in conduction velocity, suggesting poorer myelination, but no effect of conduction amplitude. In addition, we found that there was an increase in Schwann cell density, specifically immature Schwann cells, as well as a decrease in the percentage of remyelinated axons in the ablation group. Finally, macrophage targeted knock out of Gas6 in nerve injury results in an increase in Schwann cell density as well as a reduction on remyelinated internode length demonstrating that macrophage-derived Gas6 independently regulates Schwann cell dynamics in peripheral nerve injury.

Conclusion
Taken together, this dataset has enhanced our understanding of the cellular and molecular mechanisms driving macrophage-mediated recovery following nerve injury an important step towards developing more targeted treatment options.


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