title: Spinal cord reconstitution with homologous neural grafts enables robust corticospinal regeneration.
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.
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, California, USA.|Department of Orthopaedic Surgery, Hokkaido University, Sapporo, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Kadoya
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, California, USA.|Veterans Administration San Diego Healthcare System, San Diego, California, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Lu
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, California, USA.
authors.forename: Kenny
authors.initials: K
authors.lastname: Nguyen
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, California, USA.
authors.forename: Corinne
authors.initials: C
authors.lastname: Lee-Kubli
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, California, USA.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Kumamaru
authors.affiliation: Waisman Center, University of Wisconsin-Madison, Wisconsin, USA.|Department of Neuroscience, University of Wisconsin-Madison, Wisconsin, USA.|Department of Neurology, University of Wisconsin-Madison, Wisconsin, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Yao
authors.affiliation: Waisman Center, University of Wisconsin-Madison, Wisconsin, USA.|Department of Neuroscience, University of Wisconsin-Madison, Wisconsin, USA.|Department of Neurology, University of Wisconsin-Madison, Wisconsin, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Knackert
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, California, USA.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Poplawski
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, California, USA.
authors.forename: Jennifer N
authors.identifier: 0000-0001-5767-4290
authors.initials: JN
authors.lastname: Dulin
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, California, USA.
authors.forename: Hans
authors.initials: H
authors.lastname: Strobl
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, California, USA.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Takashima
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, California, USA.
authors.forename: Jeremy
authors.identifier: 0000-0001-8365-8294
authors.initials: J
authors.lastname: Biane
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, California, USA.
authors.forename: James
authors.initials: J
authors.lastname: Conner
authors.affiliation: Waisman Center, University of Wisconsin-Madison, Wisconsin, USA.
authors.forename: Su-Chun
authors.initials: SC
authors.lastname: Zhang
authors.affiliation: Department of Neurosciences, University of California, San Diego, La Jolla, California, USA.|Veterans Administration San Diego Healthcare System, San Diego, California, USA.
authors.forename: Mark H
authors.initials: MH
authors.lastname: Tuszynski
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology; D001522:Behavior, Animal; D002460:Cell Line; D002470:Cell Survival; D002574:Cervical Vertebrae; D002921:Cicatrix; D055724:Electrophysiological Phenomena; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D057026:Induced Pluripotent Stem Cells; D008297:Male; D051379:Mice; D009416:Nerve Regeneration; D058953:Neural Stem Cells / Q000378:metabolism / Q000473:pathology / Q000502:physiology / Q000637:transplantation*; D046569:Neuroepithelial Cells / Q000502:physiology; D009457:Neuroglia; D011712:Pyramidal Tracts / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D013119:Spinal Cord Injuries; D013569:Synapses / Q000502:physiology; D013904:Thoracic Vertebrae; D014184:Transplantation, Homologous