Identification of CCL3 as a Schwann cell chemotactic factor essential for nerve regeneration

Abstract

Peripheral nerves regenerate following injury, in contrast to those of the central nervous system. This involves the collective migration of Schwann cell (SC) cords, which transport regrowing axons across the wound site. The SC cords migrate along a newly formed vasculature, which bridges the wound site in response to vascular endothelial growth factor, secreted by hypoxic macrophages. However, the directional signals by which SC cords navigate the long distances across the wound, in the absence of those that guide axons during development, remain unknown. Here, we identify CCL3 as the SC chemotactic factor, secreted by hypoxic macrophages, responsible for this process. We show that CCL3 promotes collective SC migration and axonal regrowth in vivo and, using genetic mouse models and widely used CCL3 inhibitors, that CCL3 is essential for effective nerve regeneration. These findings have therapeutic implications for both promoting nerve repair and inhibiting the aberrant nerve growth associated with trauma and disease.

Keywords: CCL3; CP: Cell biology; CP: Neuroscience; Schwann cells; chemotaxis; macrophages; migration; nerve injury; neuromas; pain; peripheral nerves; regeneration.