title: The role of brain-derived neurotrophic factor in bone marrow stromal cell-mediated spinal cord repair.
abstract: 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.
authors.affiliation: Department of Physical Medicine and Rehabilitation, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Gaby J
authors.initials: GJ
authors.lastname: Ritfeld
authors.forename: Ajay
authors.initials: A
authors.lastname: Patel
authors.forename: Alexander
authors.initials: A
authors.lastname: Chou
authors.forename: Tabitha L
authors.initials: TL
authors.lastname: Novosat
authors.forename: Deborah G
authors.initials: DG
authors.lastname: Castillo
authors.forename: Raymund A C
authors.initials: RA
authors.lastname: Roos
authors.forename: Martin
authors.initials: M
authors.lastname: Oudega
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000008:administration & dosage / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D015316:Genetic Therapy; D006801:Humans; D007278:Injections, Spinal; D045164:Mesenchymal Stem Cell Transplantation; D018919:Neovascularization, Physiologic; D000066829:Neuroprotection; D051381:Rats; D017207:Rats, Sprague-Dawley; D013119:Spinal Cord Injuries / Q000235:genetics / Q000628:therapy*; D058630:Spinal Cord Regeneration
chemical_list: D019208:Brain-Derived Neurotrophic Factor