PT  - JOURNAL ARTICLE
AU  - Yi Liu
AU  - Duckhyun Kim
AU  - B. Timothy Himes
AU  - Stella Y. Chow
AU  - Timothy Schallert
AU  - Marion Murray
AU  - Alan Tessler
AU  - Itzhak Fischer
TI  - Transplants of Fibroblasts Genetically Modified to Express BDNF Promote Regeneration of Adult Rat Rubrospinal Axons and Recovery of Forelimb Function
AID  - 10.1523/JNEUROSCI.19-11-04370.1999
DP  - 1999 Jun 01
TA  - The Journal of Neuroscience
PG  - 4370--4387
VI  - 19
IP  - 11
4099  - http://www.jneurosci.org/content/19/11/4370.short
4100  - http://www.jneurosci.org/content/19/11/4370.full
SO  - J. Neurosci.1999 Jun 01; 19
AB  - 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.