Overexpression of Bcl‐X_L in human neural stem cells promotes graft survival and functional recovery following transplantation in spinal cord injury

Abstract

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.

Hydrogen-Rich Saline Protects Against Spinal Cord Injury in Rats

“…BDNF is a major source of neurotrophic factors and plays an important role in supporting the survival of neurons, enhancing the remyelination of injured axons and decreasing necrosis in SCI [17][18][19]. Increased production of BDNF from activated microglia/macrophages in the injured spinal cord leads to functional recovery as reported by others [20,21]. Our data for the first time demonstrated that hydrogen-rich saline increased the gene transcription of BDNF after spinal cord injury.…”

Hypoxic preconditioning enhances bone marrow mesenchymal stem cell migration via Kv2.1 channel and FAK activation

“…Various attempts have been made to increase cell survival after transplantation. For example, we and others have shown that overexpression of the anti-apoptotic gene bcl-2 or bcl-X L enhances cell viability after transplantation into the ischemic brain or damaged spinal cord (24,52). Trophic factors such as vascular endothelial growth factor (VEGF) coapplied with transplanted cells may have protective effects and augment therapeutic benefits (3,38).…”

Anti-apoptotic BCL-2 family proteins in acute neural injury

“…This was attenuated by exogenous administration of a BCL-X L fusion protein into the spinal cord (Nesic-Taylor et al, 2005). In addition, transplantation of neural stem cells overexpressing BCL-X L enhanced graft survival by supplying tropic factors essential for survival, and improved locomotor recovery in rats following spinal cord injury (Lee et al, 2009). …”