Intercostal nerve implants transduced with an adenoviral vector encoding neurotrophin-3 promote regrowth of injured rat corticospinal tract fibers and improve hindlimb function.
Following injury to central nervous tissues, damaged neurons are unable to regenerate their axons spontaneously. Implantation of peripheral nerves into the CNS, however, does result in axonal regeneration into these transplants and is one of the most powerful strategies to promote CNS regeneration. In the present study implantation of peripheral nerve bridges following dorsal hemisection is combined with ex vivo gene transfer with adenoviral vectors encoding neurotrophin-3 (Ad-NT-3) to examine whether this would stimulate regeneration of one of the long descending tracts of the spinal cord, the corticospinal tract (CST), into and beyond the peripheral nerve implant. We chose to use an adenoviral vector encoding NT-3 because CST axons are sensitive to this neurotrophin and Schwann cells in peripheral nerve implants do not express this neurotrophin. At 16 weeks postimplantation of Ad-NT-3-transduced intercostal nerves, approximately three- to fourfold more of the anterogradely traced corticospinal tract fibers had regrown their axons through gray matter below the lesion site when compared to control animals. Regrowth of CST fibers occurred over more than 8 mm distal to the lesion site. No regenerating CST fibers were, however, observed into the transduced peripheral implant. Animals with a peripheral nerve transduced with Ad-NT-3 also exhibited improved function of the hindlimbs when compared to control animals treated with an adenoviral vector encoding LacZ. Thus, transient overexpression of NT-3 in peripheral nerve tissue bridges is apparently sufficient to stimulate regrowth of CST fibers and to promote recovery of hindlimb function, but does not result in regeneration of CST fibers into such transplants. Taken together, combining an established neurotransplantation approach with viral vector-gene transfer promotes the regrowth of injured CST fibers through gray matter and improves the recovery of hindlimb function.
Blits
B
B
Graduate School Neurosciences Amsterdam, Netherlands Institute for Brain Research.
Dijkhuizen
P A
PA
Boer
G J
GJ
Verhaagen
J
J
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001370:Axonal Transport; D001710:Biotin / Q000031:analogs & derivatives*; D002478:Cells, Cultured; D003911:Dextrans; D005260:Female; D015870:Gene Expression; D005822:Genetic Vectors / Q000235:genetics / Q000494:pharmacology*; D006614:Hindlimb / Q000294:innervation / Q000503:physiopathology; D007367:Intercostal Nerves / Q000378:metabolism / Q000637:transplantation*; D009412:Nerve Fibers / Q000187:drug effects; D009416:Nerve Regeneration / Q000187:drug effects*; D020933:Neurotrophin 3 / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*; D011712:Pyramidal Tracts / Q000166:cytology / Q000187:drug effects* / Q000254:growth & development; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function / Q000187:drug effects; D013116:Spinal Cord / Q000166:cytology / Q000378:metabolism / Q000601:surgery; D019076:Transgenes
D003911:Dextrans; D020933:Neurotrophin 3; C076397:biotinylated dextran amine; D001710:Biotin