Reprogramming the Inflammatory Response to Promote Neural Stem Cell Function After Spinal Cord Injury

Spinal cord injury (SCI) represents a devastating neurological condition characterized by immediate mechanical damage followed by secondary pathological processes, including acute and chronic inflammation, which exacerbate neuronal loss, axonal degeneration, and glial scar formation, ultimately leading to permanent functional deficits. Emerging research highlights the dual nature of inflammation, where timely modulation can shift from a detrimental M1-like phenotype to a regenerative M2-like state, thereby fostering neural stem cell (NSC) survival and neurogenesis. Strategies for reprogramming inflammation include pharmacological interventions like minocycline or resolvins to dampen excessive cytokine storms, biomaterial scaffolds impregnated with anti-inflammatory agents to create supportive niches, and gene therapies targeting NF-κB pathways to promote anti-inflammatory signaling. Additionally, stem cell-based approaches, such as mesenchymal stem cell transplantation, secrete immunomodulatory factors that enhance NSC migration and remyelination while reducing astrogliosis. Preclinical models demonstrate that these reprogramming tactics not only mitigate secondary injury but also amplify NSC-mediated repair, improving motor recovery and sensory function. Clinical translation faces challenges like timing of intervention and personalized immunomodulation, yet holds promise for novel therapeutics. The objective of this review is to synthesize current evidence on reprogramming inflammatory pathways to optimize NSC function in SCI and to propose integrated strategies for advancing regenerative therapies.