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 Ͼ3-fold and Ͼ5-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.

Physical exercise and human adipose‐derived mesenchymal stem cells ameliorate motor disturbances in a male rat model of Parkinson's disease

“…In this study, both therapeutic approaches led to a mitigation of motor deficits, in terms of impairment of motor coordination and lack of accuracy in paw placing. However, despite the synergic effects that were described in some studies using combined treatment for traumatic pathologies in the nervous system (Hwang et al, ; Nicola et al, ), the synergistic effect on motor function in our combined group was negligible.…”

Neural stem/progenitor cell‐laden microfibers promote transplant survival in a mouse transected spinal cord injury model

“…Moreover, it must be kept in mind that cell survival or neural network formation alone may not be adequate to achieve functional recovery, as shown in previous research (Sharp et al, ). To obtain functional recovery, combined therapy with rehabilitation and/or medications should also be considered to facilitate neuronal connections and to improve the treatment effect of scaffolds (Dobrossy et al, ; Hwang et al, ).…”

Temporal and Regional Expression of Glucose-Dependent Insulinotropic Peptide and Its Receptor in Spinal Cord Injured Rats

“…33 Several studies have reported that IGF-1 attenuates the damage associated with SCI, and reduces the stress-induced tissue swelling and electrophysiological imbalance of the spinal cord. [34][35][36] An important effect of IGF-1 is its involvement with the control of axonal growth, because IGF-1 specifically enhances the extent and rate of murine corticospinal motor neuron axonal outgrowth in culture. 37 Interestingly, the incretins GIP and GLP are positive modulators of the effects of insulin, expression of IGF-1 receptor, neuronal plasticity, neurogenesis, and neuroprotection.…”