Bone Marrow Mesenchymal Stem Cells Transplantation Combined with Exercise Training Synergistically Promoted Functional Recovery After Spinal Cord Injury.

Abstract Background: Spinal cord injury (SCI) typically results in a devastating loss of neurological function below the level of injury. Although many strategies show considerable potential for SCI treatment, the therapeutic efficacy is limited. Here, we used a mouse model of thoracic contusive SCI to investigate whether the combination of bone marrow mesenchymal stem cells (BMMSCs) transplantation and exercise training has a synergistic effect on functional restoration. Methods: BMMSCs were injected directly into the contusion epicenter immediately after SCI, and the mice started treadmill training (TMT) 3 days after SCI. Locomotor function was evaluated by the Basso Mouse Scale (BMS), horizontal ladder test, and footprint analysis. Histological examination, transmission electron microscopy observation, immunofluorescence staining and western blotting were performed 8 weeks after SCI to further explore the potential mechanism of the synergistic repair effect. Results: The combination of BMMSCs transplantation and TMT showed the best therapeutic effect on motor function recovery compared with the other treatment groups. Further investigations revealed that the combination of BMMSCs transplantation and TMT markedly reduced fibrotic scar tissue, protected neurons, promoted axon and myelin regeneration, and increased synapse formation to a larger extent than either TMT or BMMSCs transplantation alone. Additionally, the synergistic effects of BMMSCs transplantation and TMT on SCI recovery occurred via activation of the PI3K/AKT/mTOR pathway. Conclusions: These findings suggest that BMMSCs transplantation combined with exercise training represents a promising combinatorial strategy to facilitate clinically meaningful recovery after SCI.