Cellular GDNF delivery promotes growth of motor and dorsal column sensory axons after partial and complete spinal cord transections and induces remyelination.
Glial cell line-derived neurotrophic factor (GDNF) is the prototypical member of a growth factor family that signals via the cognate receptors ret and GDNF-receptor alpha-1. The latter receptors are expressed on a variety of neurons that project into the spinal cord, including supraspinal neurons, dorsal root ganglia, and local neurons. Although effects of GDNF on neuronal survival in the brain have previously been reported, GDNF effects on injured axons of the adult spinal cord have not been investigated. Using an ex vivo gene delivery approach that provides both trophic support and a cellular substrate for axonal growth, we implanted primary fibroblasts genetically modified to secrete GDNF into complete and partial mid-thoracic spinal cord transection sites. Compared to recipients of control grafts expressing a reporter gene, GDNF-expressing grafts promoted significant regeneration of several spinal systems, including dorsal column sensory, regionally projecting propriospinal, and local motor axons. Local GDNF expression also induced Schwann cell migration to the lesion site, leading to remyelination of regenerating axons. Thus, GDNF exerts tropic effects on adult spinal axons and Schwann cells that contribute to axon growth after injury.
Blesch
Armin
A
Department of Neurosciences-0626, University of California-San Diego, La Jolla, California 92093-0626, USA. ablesch@ucsd.edu
Tuszynski
Mark H
MH
D000818:Animals; D001369:Axons / Q000502:physiology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000637:transplantation*; D018014:Gene Transfer Techniques; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009046:Motor Neurons / Q000502:physiology*; D009186:Myelin Sheath / Q000235:genetics / Q000502:physiology*; D009414:Nerve Growth Factors / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D009416:Nerve Regeneration / Q000235:genetics / Q000502:physiology; D009475:Neurons, Afferent / Q000502:physiology*; D018696:Neuroprotective Agents / Q000008:administration & dosage; D020671:Posterior Horn Cells / Q000254:growth & development* / Q000502:physiology; D051381:Rats; D011916:Rats, Inbred F344; D013119:Spinal Cord Injuries / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*
C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents