Differential effects of lentiviral vector-mediated overexpression of nerve growth factor and glial cell line-derived neurotrophic factor on regenerating sensory and motor axons in the transected peripheral nerve.
Even after reconstructive surgery, major functional impairments remain in the majority of patients with peripheral nerve injuries. The application of novel emerging therapeutic strategies, such as lentiviral (LV) vectors, may help to stimulate peripheral nerve regeneration at a molecular level. In the experiments described here, we examined the effect of LV vector-mediated overexpression of nerve growth factor (NGF) and glial cell line-derived neurotrophic factor (GDNF) on regeneration of the rat peripheral nerve in a transection/repair model in vivo. We showed that LV vectors can be used to locally elevate levels of NGF and GDNF in the injured rat peripheral nerve and this has profound and differential effects on regenerating sensory and motor neurons. For sensory neurons, increased levels of NGF and GDNF do not affect the number of regenerated neurons 1 cm distal to a lesion at 4 weeks post-lesion but do cause changes in the expression of markers for different populations of nociceptive neurons. These changes are accompanied by significant alterations in the recovery of nociceptive function. For motoneurons, overexpression of GDNF causes trapping of regenerating axons, impairing both long-distance axonal outgrowth and reinnervation of target muscles, whereas NGF has no effect on these parameters. These observations show the feasibility of combining surgical repair of the transected nerve with the application of viral vectors. Furthermore, they show a difference between the regenerative responses of motor and sensory neurons to locally increased levels of NGF and GDNF.
Tannemaat
Martijn R
MR
Laboratory for Neuroregeneration, Netherlands Institute for Neuroscience, Amsterdam, The Netherlands.
Eggers
Ruben
R
Hendriks
William T
WT
de Ruiter
Godard C W
GC
van Heerikhuize
Joop J
JJ
Pool
Chris W
CW
Malessy
Martijn J A
MJ
Boer
Gerard J
GJ
Verhaagen
Joost
J
D000818:Animals; D001369:Axons / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D005260:Female; D005822:Genetic Vectors / Q000627:therapeutic use*; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics; D016086:Lentivirus / Q000235:genetics*; D009046:Motor Neurons / Q000378:metabolism; D020932:Nerve Growth Factor / Q000235:genetics; D009414:Nerve Growth Factors / Q000235:genetics*; D009416:Nerve Regeneration / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009619:Nociceptors / Q000378:metabolism; D059348:Peripheral Nerve Injuries; D010525:Peripheral Nerves / Q000166:cytology / Q000378:metabolism*; D010523:Peripheral Nervous System Diseases / Q000628:therapy; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function / Q000235:genetics; D011984:Sensory Receptor Cells / Q000378:metabolism; D016896:Treatment Outcome; D015854:Up-Regulation / Q000235:genetics
D015415:Biomarkers; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D020932:Nerve Growth Factor