Full-length optic nerve regeneration in the absence of genetic manipulations

The inability of mature retinal ganglion cells (RGCs) to regenerate axons after optic nerve injury can be partially reversed by manipulating cell-autonomous and/or -nonautonomous factors. Although manipulations of cell-nonautonomous factors could have higher translational potential than genetic manipulations of RGCs, they have generally produced lower levels of optic nerve regeneration. Here, we report that preconditioning resulting from mild lens injury (conditioning LI, cLI) before optic nerve damage induced far greater regeneration than LI after nerve injury or the pro-inflammatory agent zymosan given either before or after nerve damage. Unlike zymosan-induced regeneration, cLI was unaltered by depleting mature neutrophils or T cells or blocking receptors for known inflammation-derived growth factors (oncomodulin, stromal cell-derived factor 1, CCL5) and was only partly diminished by suppressing CCR2+ monocyte recruitment. Repeated episodes of LI led to full-length optic nerve regeneration, and pharmacological removal of local resident macrophages with the colony stimulating factor 1 receptor inhibitor PLX5622 enabled some axons to reinnervate the brain in just 6 weeks, comparable to the results obtained with the most effective genetic manipulations of RGCs. Thus, cell-nonautonomous interventions can induce high levels of optic nerve regeneration, paving the way to uncovering potent, translatable therapeutic targets for CNS repair.