Functional Recovery Secondary to Neural Stem/Progenitor Cells Transplantation Combined with Treadmill Training in Mice with Chronic Spinal Cord Injury

Rapid progress in stem cell medicine is being realized in neural regeneration also in spinal cord injury (SCI). Researchers have reported remarkable functional recovery with various cell sources including induced Pluripotent Stem cell derived neural stem/progenitor cells (NS/PCs), especially in acute-to-subacute-phase animals. By contrast, most studies targeting chronic SCI concludes that NS/PC transplantation exerts only a subclinical recovery. Based on the accumulation of knowledge regarding the molecular-level effect of rehabilitative approaches, besides the pharmacological treatments are chiefly developed to improve the effect of regenerative therapy for this refractory state, physical training also have attracted the attention as a desirable candidate to combine with cell transplantation. Recently, we have reported that the addition of treadmill training enhances the effect of NS/PC transplantation for chronic SCI for the first time. In this study, we used thoracic SCI mouse models to compare manifestations secondary to both transplantation and training, and the two therapies combined, with a control group. Significant locomotor recovery in comparison with the control group was only achieved in the combined therapy group. Further investigation revealed that NS/PC transplantation improved spinal conductivity and central pattern generator activity, and that training promoted the appropriate inhibitory motor control including spasticity. The combined therapy enhanced these independent effects of each single therapy, and facilitated neuronal differentiation of transplanted cells and maturation of central pattern generator activity synergistically. Our report suggest that rehabilitative treatment represents a therapeutic option for functional recovery after NS/PC transplantation, even in chronic SCI.