title: Survival of neural stem cell grafts in the lesioned spinal cord is enhanced by a combination of treadmill locomotor training via insulin-like growth factor-1 signaling.
abstract: Combining cell transplantation with activity-based rehabilitation is a promising therapeutic approach for spinal cord repair. The present study was designed to investigate potential interactions between the transplantation (TP) of neural stem cells (NSCs) obtained at embryonic day 14 and treadmill training (TMT) in promoting locomotor recovery and structural repair in rat contusive injury model. Combination of TMT with NSC TP at 1 week after injury synergistically improved locomotor function. We report here that combining TMT increased the survival of grafted NSCs by >3-fold and >5-fold at 3 and 9 weeks after injury, respectively. The number of surviving NSCs was significantly correlated with the extent of locomotor recovery. NSCs grafted into the injured spinal cord were under cellular stresses induced by reactive nitrogen or oxygen species, which were markedly attenuated by TMT. TMT increased the concentration of insulin-like growth factor-1 (IGF-1) in the CSF. Intrathecal infusion of neutralizing IGF-1 antibodies, but not antibodies against either BDNF or Neurotrophin-3 (NT-3), abolished the enhanced survival of NSC grafts by TMT. The combination of TP and TMT also resulted in tissue sparing, increased myelination, and restoration of serotonergic fiber innervation to the lumbar spinal cord to a larger extent than that induced by either TP or TMT alone. Therefore, we have discovered unanticipated beneficial effects of TMT in modulating the survival of grafted NSCs via IGF-1. Our study identifies a novel neurobiological basis for complementing NSC-based spinal cord repair with activity-based neurorehabilitative approaches.
authors.affiliation: Department of Brain Science.
authors.forename: Dong Hoon
authors.initials: DH
authors.lastname: Hwang
authors.affiliation: Department of Brain Science, Neuroscience Graduate Program, Department of Biomedical Sciences, Ajou University School of Medicine, Suwon 443-721, Republic of Korea, and.
authors.forename: Hae Young
authors.initials: HY
authors.lastname: Shin
authors.affiliation: Department of Brain Science, Neuroscience Graduate Program, Department of Biomedical Sciences, Ajou University School of Medicine, Suwon 443-721, Republic of Korea, and.
authors.forename: Min Jung
authors.initials: MJ
authors.lastname: Kwon
authors.affiliation: Department of Brain Science, Department of Neurology, and Neuroscience Graduate Program, Department of Biomedical Sciences, Ajou University School of Medicine, Suwon 443-721, Republic of Korea, and.
authors.forename: Jun Young
authors.initials: JY
authors.lastname: Choi
authors.affiliation: Department of Animal Science and Technology, Chung-Ang University, Ansung, 456-756, Republic of Korea.
authors.forename: Buom-Yong
authors.initials: BY
authors.lastname: Ryu
authors.affiliation: Department of Brain Science, Department of Neurology, and Neuroscience Graduate Program, Department of Biomedical Sciences, Ajou University School of Medicine, Suwon 443-721, Republic of Korea, and kimbg@ajou.ac.kr.
authors.forename: Byung Gon
authors.initials: BG
authors.lastname: Kim
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology; D019208:Brain-Derived Neurotrophic Factor / Q000276:immunology; D002470:Cell Survival / Q000276:immunology / Q000502:physiology; D003131:Combined Modality Therapy / Q000379:methods; D005260:Female; D007278:Injections, Spinal; D007334:Insulin-Like Growth Factor I / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D008161:Lumbosacral Region / Q000294:innervation; D009043:Motor Activity / Q000502:physiology*; D009186:Myelin Sheath / Q000378:metabolism; D058953:Neural Stem Cells / Q000502:physiology* / Q000637:transplantation*; D020933:Neurotrophin 3 / Q000276:immunology; D051381:Rats; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D020127:Recovery of Function / Q000502:physiology; D059326:Serotonergic Neurons / Q000502:physiology; D015398:Signal Transduction; D013119:Spinal Cord Injuries / Q000378:metabolism / Q000503:physiopathology / Q000534:rehabilitation* / Q000628:therapy*; D058630:Spinal Cord Regeneration / Q000276:immunology / Q000502:physiology
chemical_list: D057134:Antibodies, Neutralizing; D019208:Brain-Derived Neurotrophic Factor; D020933:Neurotrophin 3; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D007334:Insulin-Like Growth Factor I
keywords: insulin-like growth factor-1; neural stem cell; spinal cord injury; transplantation; treadmill