Department of Brain Science.
Department of Brain Science, Neuroscience Graduate Program, Department of Biomedical Sciences, Ajou University School of Medicine, Suwon 443-721, Republic of Korea, and.
J Neurosci. 2014 Sep 17;34(38):12788-800. doi: 10.1523/JNEUROSCI.5359-13.2014.
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.
将细胞移植与基于活动的康复相结合是一种很有前途的脊髓修复治疗方法。本研究旨在探讨胚胎第 14 天获得的神经干细胞（NSC）移植（TP）与跑步机训练（TMT）在促进大鼠挫伤性损伤模型运动功能恢复和结构修复方面的潜在相互作用。TP 与损伤后 1 周开始的 TMT 相结合，协同改善运动功能。我们在此报告，TMT 可使移植的 NSCs 在损伤后 3 周和 9 周时的存活率分别增加 3 倍和 5 倍以上。存活的 NSCs 数量与运动恢复程度显著相关。移植到损伤脊髓中的 NSCs 受到活性氮或活性氧诱导的细胞应激，TMT 可显著减轻这种应激。TMT 增加了 CSF 中胰岛素样生长因子-1（IGF-1）的浓度。鞘内注射中和 IGF-1 的抗体，但不注射中和脑源性神经营养因子（BDNF）或神经营养因子-3（NT-3）的抗体，可消除 TMT 对 NSC 移植存活的增强作用。TP 和 TMT 的联合应用还导致组织保存、髓鞘形成增加以及 5-羟色胺纤维支配到腰脊髓的恢复程度大于单独使用 TP 或 TMT。因此，我们发现 TMT 通过 IGF-1 调节移植的 NSCs 存活具有意想不到的有益作用。我们的研究为通过基于活动的神经康复方法补充 NSC 为基础的脊髓修复提供了新的神经生物学基础。
