Significance: The optic nerve conveys information from retinal ganglion cells (RGCs) to visual processing areas of the brain. Although this pathway normally cannot regenerate when injured nor in degenerative diseases such as glaucoma, this failure can be partially reversed by eliciting a controlled immune reaction in the eye. We show here that the chemokine SDF1 (stromal cell–derived factor 1) is an important contributor to this phenomenon. SDF1 is produced by infiltrative monocytes and acts through its cognate receptor to enhance RGC survival, promote optic nerve regeneration, and sensitize subtypes of RGCs that normally fail to respond to a complementary treatment to exhibit robust, long-distance regeneration. These findings establish SDF1 as an important therapeutic candidate for repairing the injured optic nerve.

Oncomodulin (Ocm) is a myeloid cell–derived growth factor that enables axon regeneration in mice and rats after optic nerve injury or peripheral nerve injury, yet the mechanisms underlying its activity are unknown. Using proximity biotinylation, coimmunoprecipitation, surface plasmon resonance, and ectopic expression, we have identified armadillo-repeat protein C10 (ArmC10) as a high-affinity receptor for Ocm. ArmC10 deletion suppressed inflammation-induced axon regeneration in the injured optic nerves of mice. ArmC10 deletion also suppressed the ability of lesioned sensory neurons to regenerate peripheral axons rapidly after a second injury and to regenerate their central axons after spinal cord injury in mice (the conditioning lesion effect). Conversely, Ocm acted through ArmC10 to accelerate optic nerve and peripheral nerve regeneration and to enable spinal cord axon regeneration in these mouse nerve injury models. We showed that ArmC10 is highly expressed in human-induced pluripotent stem cell–derived sensory neurons and that exposure to Ocm altered gene expression and enhanced neurite outgrowth. ArmC10 was also expressed in human monocytes, and Ocm increased the expression of immune modulatory genes in these cells. These findings suggest that Ocm acting through its receptor ArmC10 may be a useful therapeutic target for nerve repair and immune modulation.

Although most pathways in the mature central nervous system cannot regenerate when injured, research beginning in the late 20th century has led to discoveries that may help reverse this situation. Here, we highlight research in recent years from our laboratory identifying oncomodulin (Ocm), stromal cell-derived factor (SDF)-1, and chemokine CCL5 as growth factors expressed by cells of the innate immune system that promote axon regeneration in the injured optic nerve and elsewhere in the central and peripheral nervous systems. We also review the role of ArmC10, a newly discovered Ocm receptor, in mediating many of these effects, and the synergy between inflammation-derived growth factors and complementary strategies to promote regeneration, including deleting genes encoding cell-intrinsic suppressors of axon growth, manipulating transcription factors that suppress or promote the expression of growth-related genes, and manipulating cell-extrinsic suppressors of axon growth. In some cases, combinatorial strategies have led to unprecedented levels of nerve regeneration. The identification of some similar mechanisms in human neurons offers hope that key discoveries made in animal models may eventually lead to treatments to improve outcomes after neurological damage in patients.

Study Design: Systematic review and Bayesian network meta-analysis. Objective: To compare the efficacy and safety of methylprednisolone (MP), erythropoietin (EPO), granulocyte colony-stimulating factor (G-CSF), and minocycline for the treatment of acute spinal cord injury (ASCI). Methods: MEDLINE, Embase, the Cochrane Library, and ClinicalTrials.gov were searched from inception to 15 June 2025. Randomized and nonrandomized comparative studies were eligible. Bayesian random-effects network meta-analyses compared MP, EPO, EPO plus MP, G-CSF, and minocycline. Treatment effects were reported as odds ratios (ORs) or mean differences (MDs) with 95% credible intervals (CrIs). Model convergence and fit, heterogeneity, predictive intervals, and global and local inconsistency were evaluated. Follow-up-stratified and exploratory restriction analyses were performed where feasible. Formal comparison-level Confidence in Network Meta-Analysis (CINeMA) assessment was not feasible; certainty was appraised qualitatively across its six domains. Results: Twenty comparative reports were included: nine randomized and 11 nonrandomized reports. For neurological grade improvement, G-CSF was associated with higher odds of improvement than the common control node (OR = 5.12, 95% CrI 1.15–32.42). Estimates for EPO (OR = 4.87, 95% CrI 0.44–135.90), EPO plus MP (OR = 3.44, 95% CrI 0.09–164.02), and MP (OR = 1.31, 95% CrI 0.30–5.72) were imprecise and included the null. For change in ASIA Motor Score, G-CSF had the largest point estimate (MD = 11.49, 95% CrI −0.44 to 23.49), followed by minocycline (MD = 6.83, −15.24–28.75), EPO (MD = 6.75, −13.16–26.42), and MP (MD = 2.28, −6.24–10.94); all credible intervals crossed zero. For overall adverse events, the estimate for MP was imprecise (OR = 1.13, 95% CrI 0.58–2.34), while the G-CSF effect was not reliably estimable because near-complete event occurrence produced a highly prior-sensitive posterior. Other safety estimates were imprecise. Conclusion: G-CSF showed a potential beneficial signal for neurological grade improvement. However, the limited evidence base, inclusion of nonrandomized and nonconcurrent comparisons, substantial heterogeneity, wide credible and predictive intervals, and uncertain transitivity preclude definitive conclusions about comparative efficacy or safety. Treatment rankings should be regarded as exploratory and do not establish the superiority of any intervention. Systematic Review registration: https://www.crd.york.ac.uk/PROSPERO/view/ , identifier CRD420251027856.