Clinical therapy for traumatic spinal cord injury (SCI) still remains elusive. Though new opportunities to treat brain and spinal cord trauma have been provided by marked advance made in the field of stem cell research, the progress is hindered by the complex post lesion pathology which diminishes effective donor engraftment. Using the GFAP^-/^-Vimentin^-/^- (GV) mouse model we previously demonstrated that integration of human neural stem cells (hNSCs) seeded in poly-lactic-co-glycolic scaffolds was improved in the GV spinal cord manifesting mitigated reactive gliosis following SCI. SCI GV mice receiving transplantation of hNSCs consequently showed significantly augmented functional recovery. These findings are consistent with our earlier reports that scaffolded hNSC engraftment improves locomotion in rats. Based on recent work of others and our own, indicating that plasticity of spinal intersegmental networks can trigger pivotal functional changes following SCI in rodents, we have now tested our hypothesis that post-SCI gliosis may hinder reorganization of the propriospinal neural circuits that mediate locomotor improvement after SCI by examining the impacts of double or single (d/s) knock-out of astrocytic GFAP and Vimentin on the therapeutic effects of hNSCs implant after penetrating lesion to the thoracic spinal cord. Specifically, we performed selective transection of the corticospinal tract at T2 and excitotoxic chemical lesion of propriospinal neurons at T7 in d/s KO and wildtype mice receiving scaffolded hNSC treatment. Our data indicate that recovery of locomotion in the treated GV mice largely results from reactivation of the propriospinal neuronal participation in locomotor pattern generation, which is markedly enhanced by genetic ablation of GFAP and vimentin plus the engraftment of hNSCs. The results suggest that reactive gliosis negatively affects neuroplasticity following neurotrauma, and that attenuation of reactive gliosis enhances NSC-based neuroanatomic and functional repair of traumatically injured central nervous system.

Supported by grants from NIH R21NS053935, VA Biomedical and Laboratory R&D merit grant, Massachusetts SCI Cure merit grant, the Swedish Research Council (11548), and ALF Göteborg and Hjarnfonden.