CXCR4/CXCL12-mediated entrapment of axons at the injury site compromises optic nerve regeneration

Significance Retinal ganglion cell (RGC) axons in the optic nerve convey visual information from the eye to the brain. Injury causes permanent functional loss as axons cannot regenerate. This failure is generally attributed to an insufficient intrinsic regenerative capacity, the extrinsic inhibitory environment, and RGC death. Here, we show that a chemoattractive CXCL12/CXCR4-dependent mechanism entraps growth-stimulated axons at the lesion site, thereby limiting axon extension in the nerve. Accordingly, specific depletion of either CXCR4 or CXCL12 in growth-stimulated RGCs releases entrapped axons and markedly enhances nerve regeneration at long distances. Thus, active CXCL12/CXCR4-mediated attraction to the injury site represents a mechanism preventing central nervous system (CNS) axon regeneration. Moreover, treatments targeting CXCL12/CXCR4 signaling may be promising approaches to improve CNS repair.