Abstract

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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Acknowledgements

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.).

Author information

Affiliations

  1. Department of Neurosciences, University of California, San Diego, La Jolla, California, USA.

    • Ken Kadoya
    • , Paul Lu
    • , Kenny Nguyen
    • , Corinne Lee-Kubli
    • , Hiromi Kumamaru
    • , Gunnar Poplawski
    • , Jennifer N Dulin
    • , Hans Strobl
    • , Yoshio Takashima
    • , Jeremy Biane
    • , James Conner
    •  & Mark H Tuszynski
  2. Department of Orthopaedic Surgery, Hokkaido University, Sapporo, Japan.

    • Ken Kadoya
  3. Veterans Administration San Diego Healthcare System, San Diego, California, USA.

    • Paul Lu
    •  & Mark H Tuszynski
  4. Waisman Center, University of Wisconsin–Madison, Wisconsin, USA.

    • Lin Yao
    • , Joshua Knackert
    •  & Su-Chun Zhang
  5. Department of Neuroscience, University of Wisconsin–Madison, Wisconsin, USA.

    • Lin Yao
    •  & Joshua Knackert
  6. Department of Neurology, University of Wisconsin–Madison, Wisconsin, USA.

    • Lin Yao
    •  & Joshua Knackert

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Contributions

K.K. conceived and carried out experiments, interpreted the results and wrote the manuscript. P.L. contributed to the conception of the project and performed complete-transection experiments. K.N. and H.S. carried out experiments. C.L.-K. and J.N.D. contributed to behavior analysis. G.P. contributed to mouse experiments. H.K. contributed to the characterization of human NPCs. L.Y., J.K. and S.-C.Z. contributed to the generation of human NPCs from iPSCs. J.B., Y.T. and J.C. performed the electrophysiological analysis. M.H.T. contributed to the conception of the project and the interpretation of results, and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Mark H Tuszynski.

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DOI

https://doi.org/10.1038/nm.4066