Home LiteratureArticle Details
PMID: 19874785 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Combined intrinsic and extrinsic neuronal mechanisms facilitate bridging axonal regeneration one year after spinal cord injury.

Neuron ·Vol. 64 ·No. 2 ·2009-10-29 ·Pages 165-72

Kadoya K, Tsukada S, Lu P, Coppola G, Geschwind D, Filbin MT, Blesch A, Tuszynski MH

Abstract

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.

MeSH Terms
Analysis of Variance Animals Axons/drug effects,physiology Bone Marrow Transplantation/physiology Cells, Cultured Cholera Toxin Disease Models, Animal Female GAP-43 Protein/metabolism Ganglia, Spinal/cytology Gene Expression Profiling/methods Glial Fibrillary Acidic Protein/metabolism Green Fluorescent Proteins/genetics,metabolism Nerve Regeneration/drug effects,physiology Nerve Tissue Proteins/metabolism Neurotrophin 3/therapeutic use Oligonucleotide Array Sequence Analysis/methods Proto-Oncogene Proteins c-jun/metabolism Rats Rats, Inbred F344 Sensory Receptor Cells/drug effects,metabolism Spinal Cord Injuries/pathology,physiopathology,therapy Time Factors
Chemicals
GAP-43 Protein Glial Fibrillary Acidic Protein Nerve Tissue Proteins Neurotrophin 3 Proto-Oncogene Proteins c-jun Green Fluorescent Proteins Cholera Toxin
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Kadoya Ken
Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
Tsukada Shingo
Lu Paul
Coppola Giovanni
Geschwind Dan
Filbin Marie T
Blesch Armin
Tuszynski Mark H
References (23)
23 references, click to expand
  1. Repair of chronic spinal cord injury.
    Exp Neurol. 2003 Aug;182(2):247-60 PMID: 12895437
  2. The role of extracellular matrix in CNS regeneration.
    Curr Opin Neurobiol. 2007 Feb;17(1):120-7 PMID: 17223033
  3. Bridging areas of injury in the spinal cord.
    Neuroscientist. 2001 Aug;7(4):325-39 PMID: 11488398
  4. cAMP and Schwann cells promote axonal growth and functional recovery after spinal cord injury.
    Nat Med. 2004 Jun;10(6):610-6 PMID: 15156204
  5. Regeneration of dorsal column fibers into and beyond the lesion site following adult spinal cord injury.
    Neuron. 1999 May;23(1):83-91 PMID: 10402195
  6. Neurotrophin-3 gradients established by lentiviral gene delivery promote short-distance axonal bridging beyond cellular grafts in the injured spinal cord.
    J Neurosci. 2006 Sep 20;26(38):9713-21 PMID: 16988042
  7. A transcription-dependent switch controls competence of adult neurons for distinct modes of axon growth.
    J Neurosci. 1997 Jan 15;17(2):646-58 PMID: 8987787
  8. Regeneration of sensory axons within the injured spinal cord induced by intraganglionic cAMP elevation.
    Neuron. 2002 Jun 13;34(6):885-93 PMID: 12086637
  9. Spinal axon regeneration induced by elevation of cyclic AMP.
    Neuron. 2002 Jun 13;34(6):895-903 PMID: 12086638
  10. NT-3 gene delivery elicits growth of chronically injured corticospinal axons and modestly improves functional deficits after chronic scar resection.
    Exp Neurol. 2003 May;181(1):47-56 PMID: 12710933
  11. Engraftment and migration of human bone marrow stromal cells implanted in the brains of albino rats--similarities to astrocyte grafts.
    Proc Natl Acad Sci U S A. 1998 Mar 31;95(7):3908-13 PMID: 9520466
  12. Conditioning injury-induced spinal axon regeneration requires signal transducer and activator of transcription 3 activation.
    J Neurosci. 2005 Feb 16;25(7):1645-53 PMID: 15716400
  13. Combining an autologous peripheral nervous system "bridge" and matrix modification by chondroitinase allows robust, functional regeneration beyond a hemisection lesion of the adult rat spinal cord.
    J Neurosci. 2006 Jul 12;26(28):7405-15 PMID: 16837588
  14. Inflammatory-mediated injury and repair in the traumatically injured spinal cord.
    Curr Pharm Des. 2005;11(10):1223-36 PMID: 15853679
  15. Overcoming inhibition in the damaged spinal cord.
    J Neurotrauma. 2006 Mar-Apr;23(3-4):371-83 PMID: 16629623
  16. Combinatorial therapy with neurotrophins and cAMP promotes axonal regeneration beyond sites of spinal cord injury.
    J Neurosci. 2004 Jul 14;24(28):6402-9 PMID: 15254096
  17. Myelin-associated inhibitors of axonal regeneration in the adult mammalian CNS.
    Nat Rev Neurosci. 2003 Sep;4(9):703-13 PMID: 12951563
  18. Survival and regeneration of rubrospinal neurons 1 year after spinal cord injury.
    Proc Natl Acad Sci U S A. 2002 Mar 5;99(5):3246-51 PMID: 11867727
  19. Axonal regeneration and functional recovery after complete spinal cord transection in rats by delayed treatment with transplants and neurotrophins.
    J Neurosci. 2001 Dec 1;21(23):9334-44 PMID: 11717367
  20. Fibroblasts genetically modified to produce BDNF support regrowth of chronically injured serotonergic axons.
    Neurorehabil Neural Repair. 2000;14(4):311-7 PMID: 11402881
  21. The AP-1 transcription factor c-Jun is required for efficient axonal regeneration.
    Neuron. 2004 Jul 8;43(1):57-67 PMID: 15233917
  22. Neurotrophic factors, cellular bridges and gene therapy for spinal cord injury.
    J Physiol. 2001 May 15;533(Pt 1):83-9 PMID: 11351016
  23. Retrograde degeneration of corticospinal axons following transection of the spinal cord in rats. A quantitative study with anterogradely transported horseradish peroxidase.
    J Neurosurg. 1988 Jan;68(1):124-8 PMID: 3335897
Article Info
Journal
Neuron
Abbr.
Neuron
ISSN
1097-4199
DOI
10.1016/j.neuron.2009.09.016
Published
2009-10-29
Pages
165-72
Language
English
Region
United States
NLM ID
8809320
PMCID
PMC2773653
Subset
IM
Grants
NINDS NIH HHS · R01 NS049881-01 · United States
NINDS NIH HHS · R01 NS049881-02 · United States
NINDS NIH HHS · F31 NS009881 · United States
NINDS NIH HHS · R01 NS054883 · United States
NINDS NIH HHS · R01 NS09881 · United States
NINDS NIH HHS · R01 NS049881-04 · United States
NINDS NIH HHS · R01 NS049881-03 · United States
NINDS NIH HHS · NS054883 · United States
NINDS NIH HHS · R01 NS049881 · United States
NINDS NIH HHS · R01 NS054883-03 · United States
External Links
PubMed source DOI: 10.1016/j.neuron.2009.09.016 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2