Transplants of fibroblasts expressing BDNF and NT-3 promote recovery of bladder and hindlimb function following spinal contusion injury in rats.
We examined whether fibroblasts, genetically modified to express BDNF and NT-3 (Fb-BDNF/NT3) and transplanted into a thoracic spinal injury site, would enhance recovery of bladder function and whether this treatment would be associated with reorganization of lumbosacral spinal circuits implicated in bladder function. Rats received modified-moderate contusion injuries at T8/9, and 9 days later, Fb-BDNF/NT3 or unmodified fibroblasts (OP-controls) were delivered into the cord. Fb-BDNF/NT3 rats recovered from areflexic bladder earlier, showed decreased micturition pressure and fewer episodes of detrusor hyperreflexia, compared to OP-controls. There were also improvements in hindlimb function in the Fb-BDNF/NT3 group although locomotion on a more challenging substrate (grid) and tail withdrawal latency in response to a thermal stimulus showed persisting deficits, little recovery, and no differences between the groups. Immunocytochemistry at L6-S1 revealed changes in density of afferent and descending projections to L6-S1 cord. The density of small dorsal root axons increased in the superficial layers of the dorsal horn in OP-controls but not in Fb-BDNF/NT3, suggesting sprouting of primary afferents following injury that was inhibited by Fb-BDNF/NT-3. In contrast, the trophic factor secreting transplants stimulated sprouting and/or sparing of descending modulatory pathways projecting to the lumbosacral spinal cord. No differences in synaptophysin immunoreactivity were seen in the dorsal horn which suggested that synaptic density was similar but achieved by sprouting of different systems in the two operated groups. Fb-BDNF/NT3 transplanted into injured spinal cord thus improved both bladder and hindlimb function, and this was associated with reorganization of spinal circuitry.
Mitsui
Takahiko
T
Department of Neurobiology and Anatomy, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, PA 19129, USA.
Fischer
Itzhak
I
Shumsky
Jed S
JS
Murray
Marion
M
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000637:transplantation*; D020439:Growth Cones / Q000502:physiology / Q000648:ultrastructure; D006614:Hindlimb / Q000294:innervation / Q000503:physiopathology; D009416:Nerve Regeneration / Q000502:physiology; D009434:Neural Pathways / Q000503:physiopathology; D020933:Neurotrophin 3 / Q000235:genetics* / Q000378:metabolism; D017288:Pain Threshold / Q000502:physiology; D010243:Paralysis / Q000209:etiology / Q000503:physiopathology / Q000628:therapy; D017729:Presynaptic Terminals / Q000378:metabolism / Q000648:ultrastructure; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000235:genetics*; D013116:Spinal Cord / Q000473:pathology / Q000503:physiopathology; D013119:Spinal Cord Injuries / Q000150:complications / Q000503:physiopathology / Q000628:therapy*; D013126:Spinal Nerve Roots / Q000166:cytology / Q000502:physiology; D014162:Transfection; D001750:Urinary Bladder, Neurogenic / Q000209:etiology / Q000503:physiopathology / Q000628:therapy
D019208:Brain-Derived Neurotrophic Factor; D020933:Neurotrophin 3