Efficient generation of human dorsal spinal GABAergic progenitors for the treatment of spinal cord injury.

Traumatic spinal cord injury (SCI) induces rapid necrotic cell death, leading to severe neuronal and glial loss. A critical consequence is the disruption of γ-aminobutyric acid (GABA)ergic inhibitory tone in the dorsal horn, which results in excessive glutamate release and neuronal hyperexcitability-a hallmark of central neuropathic pain and excitotoxicity that exacerbates secondary spinal damage. Notably, GABA itself exhibits neuroprotective properties, mitigating secondary injury and promoting neurite outgrowth during development or after central nervous system trauma. Whereas human neural stem cell-based therapies hold promise for compensating neuronal loss after SCI, their efficacy is limited by the hostile injury microenvironment and default differentiation pathways, which restrict the generation of mature, dorsal spinal GABAergic neurons. Here we identified key transcription factors that rapidly convert human pluripotent stem cells into dorsal spinal GABAergic progenitors with high efficiency. These induced GABAergic progenitors demonstrated remarkable resilience in the injured microenvironment, exhibiting intrinsic capacity to generate mature GABAergic neurons for functional integration. Importantly, they also exert noncell autonomous effects, reducing apoptosis, inhibiting glial scar formation and stimulating neurogenesis of endogenous cells following SCI. On integration into host neural circuitry and niche rewiring, induced GABAergic progenitor grafts significantly improved central neuropathic pain as early as 6 weeks after grafting and enhanced locomotor activities, demonstrating their great potential for future clinical applications in SCI treatment.