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.

Cell (13 August 2015) doi:10.1016/j.cell.2015.07.021