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 murine 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 SCI. Corticospinal regeneration requires grafts to be 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, a process that is potentially related to the attenuation of the glial scar. Rat 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 SCI research and offering new possibilities for clinical translation.
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We thank L. Graham, Y. Yang, E. Boehle, J.K. Lee, M. Kim, E. Liu, R. Pope and T. Moynihan for their technical assistance; Planned Parenthood; the Rat Resource and Research Center, University of Missouri, Columbia, Missouri, for providing GFP rats; James Thompson at the University of Wisconsin–Madison, for providing hiPSC line IMR90; K. Wewetzer, University of Freiburg, Germany, for providing 27C7 antibody; R. Darnell, the Rockefeller University, New York, for providing Hu antibody; Y. Jones for use of the electron-microscopy core facility at Cellular and Molecular Medicine, University of California, San Diego; and the Nikon Imaging Center at Hokkaido University for use of the confocal laser microscope. This work was supported by the US Veterans Administration (Gordon Mansfield Spinal Cord Injury Consortium; to M.H.T. and P.L.) the US National Institutes of Health (NS042291 to M.H.T. and GM008349 to J.K.); the Craig H. Neilsen Foundation (to K.K., H.K. and J.N.D.); the Bernard and Anne Spitzer Charitable Trust (to M.H.T.); the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (to M.H.T. and J.C.); Kobayashi Hospital Furate Research Fund (to K.K.); the Japan Society for the Promotion of Science (to H.K.); and the Busta Family and Bleser Family funds (to S.C.Z.).
The authors declare no competing financial interests.
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Kadoya, K., Lu, P., Nguyen, K. et al. Spinal cord reconstitution with homologous neural grafts enables robust corticospinal regeneration. Nat Med 22, 479–487 (2016). https://doi.org/10.1038/nm.4066
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