The role of brain-derived neurotrophic factor in bone marrow stromal cell-mediated spinal cord repair.
Ritfeld GJ, Patel A, Chou A, Novosat TL, Castillo DG, Roos RA, Oudega M
The ability of intraspinal bone marrow stromal cell (BMSC) transplants to elicit repair is thought to result from paracrine effects by secreted trophic factors including brain-derived neurotrophic factor (BDNF). Here we used gene therapy to increase or silence BDNF production in BMSCs to investigate the role of BDNF in BMSC-mediated neuroprotection. In a spinal cord organotypic culture, BMSC conditioned medium significantly enhanced spinal motoneuron survival by 64% compared with culture medium only. Only conditioned medium of BDNF-hypersecreting BMSCs sustained this neuroprotective effect. In a rat model of spinal cord contusion, a BDNF-dependent neuroprotective effect was confirmed; only with a sub-acute transplant of BDNF-hypersecreting BMSCs significantly more spared motoneurons were found at four weeks post-injury compared with vehicle controls. Spared nervous tissue volume was improved by 68% with both control BMSCs and BDNF-hypersecreting BMSCs. In addition, blood vessel density in the contusion with BDNF-hypersecreting BMSCs was 35% higher compared with BMSC controls and 6-fold higher compared with vehicle controls. BDNF-silenced BMSCs did not survive the first week of transplantation and no neuroprotective effect was found at four weeks after transplantation. Together, our data broaden our understanding of the role of BDNF in BMSC-mediated neuroprotection, and successfully exploit BDNF-dependency to enhance anatomical spinal cord repair.