Combined intrinsic and extrinsic neuronal mechanisms facilitate bridging axonal regeneration one year after spinal cord injury.
Despite advances in promoting axonal regeneration after acute spinal cord injury (SCI), elicitation of bridging axon regeneration after chronic SCI remains a formidable challenge. We report that combinatorial therapies administered 6 weeks, and as long as 15 months, after SCI promote axonal regeneration into and beyond a midcervical lesion site. Provision of peripheral nerve conditioning lesions, grafts of marrow stromal cells, and establishment of NT-3 gradients supports bridging regeneration. Controls receiving partial components of the full combination fail to exhibit bridging. Notably, intraneuronal molecular mechanisms recruited by delayed therapies mirror those of acute injury, including activation of transcriptional activators and regeneration-associated genes. Collectively, these findings provide evidence that regeneration is achievable at unprecedented postinjury time points.
Kadoya
Ken
K
Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
Tsukada
Shingo
S
Lu
Paul
P
Coppola
Giovanni
G
Geschwind
Dan
D
Filbin
Marie T
MT
Blesch
Armin
A
Tuszynski
Mark H
MH
D000704:Analysis of Variance; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000502:physiology*; D016026:Bone Marrow Transplantation / Q000502:physiology; D002478:Cells, Cultured; D002772:Cholera Toxin; D004195:Disease Models, Animal; D005260:Female; D019922:GAP-43 Protein / Q000378:metabolism; D005727:Ganglia, Spinal / Q000166:cytology; D020869:Gene Expression Profiling / Q000379:methods; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D020933:Neurotrophin 3 / Q000627:therapeutic use; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism; D013119:Spinal Cord Injuries / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D013997:Time Factors
D019922:GAP-43 Protein; D005904:Glial Fibrillary Acidic Protein; D009419:Nerve Tissue Proteins; D020933:Neurotrophin 3; D016755:Proto-Oncogene Proteins c-jun; D049452:Green Fluorescent Proteins; D002772:Cholera Toxin