The Role of Brain-Derived Neurotrophic Factor in Bone Marrow Stromal Cell-Mediated Spinal Cord Repair
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...
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doaj-3a8faca6d5ee4b35b28fca6d3423af882020-11-25T03:10:04ZengSAGE PublishingCell Transplantation0963-68971555-38922015-11-012410.3727/096368915X686201The Role of Brain-Derived Neurotrophic Factor in Bone Marrow Stromal Cell-Mediated Spinal Cord RepairGaby J. Ritfeld0Ajay Patel1Alexander Chou2Tabitha L. Novosat3Deborah G. Castillo4Raymund A. C. Roos5Martin Oudega Ph.D.6Department of Neurology, Leiden University Medical Center, Leiden, The NetherlandsCarnegie Mellon University, Pittsburgh, PA, USACarnegie Mellon University, Pittsburgh, PA, USADepartment of Physical Medicine and Rehabilitation, University of Pittsburgh School of Medicine, Pittsburgh, PA, USADepartment of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USADepartment of Neurology, Leiden University Medical Center, Leiden, The NetherlandsDepartment of Bioengineering, University of Pittsburgh School of Medicine, Pittsburgh, PA, USAThe 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.https://doi.org/10.3727/096368915X686201 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Gaby J. Ritfeld Ajay Patel Alexander Chou Tabitha L. Novosat Deborah G. Castillo Raymund A. C. Roos Martin Oudega Ph.D. |
spellingShingle |
Gaby J. Ritfeld Ajay Patel Alexander Chou Tabitha L. Novosat Deborah G. Castillo Raymund A. C. Roos Martin Oudega Ph.D. The Role of Brain-Derived Neurotrophic Factor in Bone Marrow Stromal Cell-Mediated Spinal Cord Repair Cell Transplantation |
author_facet |
Gaby J. Ritfeld Ajay Patel Alexander Chou Tabitha L. Novosat Deborah G. Castillo Raymund A. C. Roos Martin Oudega Ph.D. |
author_sort |
Gaby J. Ritfeld |
title |
The Role of Brain-Derived Neurotrophic Factor in Bone Marrow Stromal Cell-Mediated Spinal Cord Repair |
title_short |
The Role of Brain-Derived Neurotrophic Factor in Bone Marrow Stromal Cell-Mediated Spinal Cord Repair |
title_full |
The Role of Brain-Derived Neurotrophic Factor in Bone Marrow Stromal Cell-Mediated Spinal Cord Repair |
title_fullStr |
The Role of Brain-Derived Neurotrophic Factor in Bone Marrow Stromal Cell-Mediated Spinal Cord Repair |
title_full_unstemmed |
The Role of Brain-Derived Neurotrophic Factor in Bone Marrow Stromal Cell-Mediated Spinal Cord Repair |
title_sort |
role of brain-derived neurotrophic factor in bone marrow stromal cell-mediated spinal cord repair |
publisher |
SAGE Publishing |
series |
Cell Transplantation |
issn |
0963-6897 1555-3892 |
publishDate |
2015-11-01 |
description |
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. |
url |
https://doi.org/10.3727/096368915X686201 |
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