The corticospinal tract (CST) is the most important motor system in humans, yet robust regeneration of this projection after spinal cord injury (SCI) has not been accomplished. In rodent models of SCI, we report robust corticospinal axon regeneration, functional synapse formation and improved skilled forelimb function after grafting multipotent neural progenitor cells into sites of spinal cord injury. Corticospinal regeneration requires that grafts are driven toward caudalized (spinal cord), rather than rostralized, fates. Fully mature caudalized neural grafts also support corticospinal regeneration. Moreover, corticospinal axons can emerge from neural grafts and regenerate beyond the lesion, potentially related to attenuation of the glial scar. Rodent corticospinal axons also regenerate into human donor grafts of caudal spinal cord identity. Collectively, these findings indicate that spinal cord “replacement” with homologous neural stem cells enables robust regeneration of the corticospinal projection within and beyond spinal cord lesion sites, achieving a major unmet goal of spinal cord injury research and opening new possibilities for translation.

Thirty-six rats have received surgical spinal cord lesions, 7 at a thoracic and 29 at a cervical level. More than 70% of rats with lesions which involved the lateral column (spinothalamic tract) developed spontaneous dysesthesias in the contralateral limb. Only high cervical (C1-C2) lateral column lesions were followed frequently by forelimb signs. Lesions restricted to the dorsal columns were not followed by dysesthesias.

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