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Previous Article | Next Article
The Journal of Neuroscience, June 1, 1999, 19(11):4370-4387
Transplants of Fibroblasts Genetically Modified to Express BDNF Promote Regeneration of Adult Rat Rubrospinal Axons and Recovery of Forelimb Function
Yi Liu1, Duckhyun Kim1, B. Timothy Himes1, 2, Stella Y. Chow1, Timothy Schallert3, Marion Murray1, Alan Tessler1, 2, and Itzhak Fischer1 1 Department of Neurobiology and Anatomy, Medical College of Pennsylvania/Hahnemann University, Philadelphia, Pennsylvania 19129, 2 Philadelphia Veterans Administration Hospital, Philadelphia, Pennsylvania 19104, and 3 Department of Psychology and Institute for Neuroscience, University of Texas at Austin, Austin, Texas 78712
Adult mammalian CNS neurons do not normally regenerate their severed axons. This failure has been attributed to scar tissue and inhibitory molecules at the injury site that block the regenerating axons, a lack of trophic support for the axotomized neurons, and intrinsic neuronal changes that follow axotomy, including cell atrophy and death. We studied whether transplants of fibroblasts genetically engineered to produce brain-derived neurotrophic factor (BDNF) would promote rubrospinal tract (RST) regeneration in adult rats. Primary fibroblasts were modified by retroviral-mediated transfer of a DNA construct encoding the human BDNF gene, an internal ribosomal entry site, and a fusion gene of lacZ and neomycin resistance genes. The modified fibroblasts produce biologically active BDNF in vitro. These cells were grafted into a partial cervical hemisection cavity that completely interrupted one RST. One and two months after lesion and transplantation, RST regeneration was demonstrated with retrograde and anterograde tracing techniques. Retrograde tracing with fluorogold showed that ~7% of RST neurons regenerated axons at least three to four segments caudal to the transplants. Anterograde tracing with biotinylated dextran amine revealed that the RST axons regenerated through and around the transplants, grew for long distances within white matter caudal to the transplant, and terminated in spinal cord gray matter regions that are the normal targets of RST axons. Transplants of unmodified primary fibroblasts or Gelfoam alone did not elicit regeneration. Behavioral tests demonstrated that recipients of BDNF-producing fibroblasts showed significant recovery of forelimb usage, which was abolished by a second lesion that transected the regenerated axons.
Key words: spinal cord injury; cell transplantation; retrovirus; axon regeneration; anterograde tracing; retrograde tracing; neurotrophin; recovery of function
Copyright © 1999 Society for Neuroscience 0270-6474/99/19114370-18$05.00/0
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