Background: Contusive spinal cord injury is complicated by a delayed loss of oligodendrocytes, resulting in chronic progressive demyelination. Therefore, transplantation strategies to provide oligodendrocyte lineage cells and to enhance the extent of myelination appear to be justified for spinal cord repair. The present study investigated whether transplantation of human neural stem cells (NSCs) genetically modified to express Olig2 transcription factor, an essential regulator of oligodendrocyte development, can improve locomotor recovery and enhance myelination in a rat contusive spinal cord injury model.

Transplantation of neural stem cells (NSCs) has shown promise for improving functional recovery after spinal cord injury (SCI). The inhospitable milieu of injured spinal cord, however, does not support survival of grafted NSCs, reducing therapeutic efficacy of transplantation. The present study sought to examine whether overexpression of antiapoptotic gene Bcl-X L in NSCs could promote graft survival and functional recovery following transplantation in rat contusive SCI model. A human NSC line (HB1.F3) was transduced with a retroviral vector encoding Bcl-X L to generate Bcl-X L -overexpressing NSCs (HB1.F3.Bcl-X L ). Overexpression of Bcl-X L conferred resistance to staurosporine-mediated apoptosis. The number of HB1.F3.Bcl-X L cells was 1.5-fold higher at 2 weeks and 10-fold higher at 7 weeks posttransplantation than that of HB1.F3 cells. There was no decline in the number of HB1.F3.Bcl-X L cells between 2 and 7 weeks, indicating that Bcl-X L overexpression completely blocked cell death occurring between these two time points. Transplantation of HB1.F3.Bcl-X L cells improved locomotor scores and enhanced accuracy of hindlimb placement in a grid walk. Approximately 10% of surviving NSCs differentiated into oligodendrocytes. Surviving NSCs produced brain-derived neurotrophic factor (BDNF), and the level of BDNF was significantly increased only in the HB1.F3.Bcl-X L group. Transplantation of HB1.F3.Bcl-X L cells reduced cavity volumes and enhanced white matter sparing. Finally, HB1.F3.Bcl-X L grafts enhanced connectivity between the red nucleus and the spinal cord below the lesion. These results suggest that enhancing graft survival with antiapoptotic gene can potentiate therapeutic benefits of NSC-based therapy for SCI. V V C 2009 Wiley-Liss, Inc.