Journal
CELL TRANSPLANTATION
Volume 24, Issue 11, Pages 2209-2220Publisher
COGNIZANT COMMUNICATION CORP
DOI: 10.3727/096368915X686201
Keywords
Spinal cord injury; Bone marrow stromal cells (BMSCs); Neuroprotection; Blood vessels; Brain-derived neurotrophic factor (BDNF); Gene therapy
Funding
- LUMC [30229/5000]
- Wings for Life Foundation [WFL-US-015/13]
- Craig H. Nielsen Foundation [284621]
- Department of Physical Medicine and Rehabilitation at the University of Pittsburgh
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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 subacute transplant of BDNF-hypersecreting BMSCs were significantly more spared motoneurons found at 4 weeks postinjury 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 sixfold higher compared with vehicle controls. BDNF-silenced BMSCs did not survive the first week of transplantation, and no neuroprotective effect was found at 4 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.
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