The regeneration of fully cut peripheral nerves requires the Schwann cell–guided regrowth of axons across bridges formed by a mixture of cells of the immune system and connective-tissue cells. In Cell, Lloyd and colleagues show that macrophages specifically sense hypoxia within the bridge environment and secrete VEGF-A to induce polarized vascularization of the bridge. The bridge is fully vascularized before the migration of Schwann cells, which closely adhere to the endothelial cell scaffold and use it as a guiding path for migration. Endothelial cells migrate in response to VEGF-A, but Schwann cells do not. Deletion of VEGF-A specifically in macrophages diminishes vascularization of the bridge and confines Schwann cells to the nerve stumps, while ectopic VEGF-A signals from the muscle mass misdirect the blood vessels, the Schwann cell cords and the axons. Thus, macrophages sense the conditions in the injured nerve and initiate the regeneration process.
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Visan, I. Guiding nerve regeneration. Nat Immunol 16, 1013 (2015). https://doi.org/10.1038/ni.3283