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Development-inspired glial reprogramming drives functional recovery after spinal cord injury

ABSTRACT: Spinal cord injury (SCI) causes irreversible neuronal loss and circuit disruption, with cervical lesions severely impairing forelimb function. Here, we identify a development-inspired reprogramming strategy that enables adult glia to generate neurons capable of reconstructing spinal circuits and restoring motor control. In vivo screening reveals that the activator form of GLI3 (GLI3A) is a potent enhancer of SOX2-mediated reprogramming. SOX2-GLI3A rapidly converts resident glia into progenitors and neurons, overcoming the stalling observed with SOX2 alone. Single-cell RNA sequencing shows multilineage potential but a strong neurogenic bias, with enrichment of axon guidance and synaptogenesis programs. Lineage tracing and circuit mapping demonstrate that induced neurons integrate into propriospinal and supraspinal motor pathways and establish connections with forelimb muscles. Functionally, SOX2-GLI3A reprogramming restores forelimb coordination and improves fine paw kinematics after severe cervical SCI. These findings establish a regenerative strategy that unlocks the neurogenic potential of adult glia to drive meaningful repair.

ORGANISM(S): Mus musculus

PROVIDER: GSE344367 | GEO | 2026/08/21

REPOSITORIES: GEO

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Development-inspired glial reprogramming drives functional recovery after spinal cord injury

Project description:Spinal cord injury (SCI) causes irreversible neuronal loss and circuit disruption, with cervical lesions severely impairing forelimb function. Here, we identify a development-inspired reprogramming strategy that enables adult glia to generate neurons capable of reconstructing spinal circuits and restoring motor control. In vivo screening reveals that the activator form of GLI3 (GLI3A) is a potent enhancer of SOX2-mediated reprogramming. SOX2-GLI3A rapidly converts resident glia into progenitors and neurons, overcoming the stalling observed with SOX2 alone. Single-cell RNA sequencing shows multilineage potential but a strong neurogenic bias, with enrichment of axon guidance and synaptogenesis programs. Lineage tracing and circuit mapping demonstrate that induced neurons integrate into propriospinal and supraspinal motor pathways and establish connections with forelimb muscles. Functionally, SOX2-GLI3A reprogramming restores forelimb coordination and improves fine paw kinematics after severe cervical SCI. These findings establish a regenerative strategy that unlocks the neurogenic potential of adult glia to drive meaningful repair.

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