title: Expression of an Activated Integrin Promotes Long-Distance Sensory Axon Regeneration in the Spinal Cord.
abstract: After CNS injury, axon regeneration is blocked by an inhibitory environment consisting of the highly upregulated tenascin-C and chondroitin sulfate proteoglycans (CSPGs). Tenascin-C promotes growth of axons if they express a tenascin-binding integrin, particularly α9β1. Additionally, integrins can be inactivated by CSPGs, and this inhibition can be overcome by the presence of a β1-binding integrin activator, kindlin-1. We examined the synergistic effect of α9 integrin and kindlin-1 on sensory axon regeneration in adult rat spinal cord after dorsal root crush and adeno-associated virus transgene expression in dorsal root ganglia. After 12 weeks, axons from C6-C7 dorsal root ganglia regenerated through the tenascin-C-rich dorsal root entry zone into the dorsal column up to C1 level and above (>25 mm axon length) through a normal pathway. Animals also showed anatomical and electrophysiological evidence of reconnection to the dorsal horn and behavioral recovery in mechanical pressure, thermal pain, and ladder-walking tasks. Expression of α9 integrin or kindlin-1 alone promoted much less regeneration and recovery.
  
  
  
  The study demonstrates that long-distance sensory axon regeneration over a normal pathway and with sensory and sensory-motor recovery can be achieved. This was achieved by expressing an integrin that recognizes tenascin-C, one of the components of glial scar tissue, and an integrin activator. This enabled extensive long-distance (>25 mm) regeneration of both myelinated and unmyelinated sensory axons with topographically correct connections in the spinal cord. The extent of growth and recovery we have seen would probably be clinically significant. Restoration of sensation to hands, perineum, and genitalia would be a significant improvement for a spinal cord-injured patient.
authors.affiliation: John van Geest Centre for Brain Repair, University of Cambridge, Cambridge CB2 0PY, United Kingdom.
authors.forename: Menghon
authors.initials: M
authors.lastname: Cheah
authors.affiliation: School of Medicine, University of St. Andrews, St. Andrews KY16 9TF, United Kingdom, mra5@st-andrews.ac.uk jf108@cam.ac.uk.
authors.forename: Melissa R
authors.identifier: 0000-0001-5960-5619
authors.initials: MR
authors.lastname: Andrews
authors.affiliation: John van Geest Centre for Brain Repair, University of Cambridge, Cambridge CB2 0PY, United Kingdom.
authors.forename: Daniel J
authors.identifier: 0000-0002-5391-9630
authors.initials: DJ
authors.lastname: Chew
authors.affiliation: Laboratory for Neuroregeneration, Netherlands Institute for Neuroscience, 1105 BA, Amsterdam, The Netherlands, and.
authors.forename: Elizabeth B
authors.identifier: 0000-0003-0746-5081
authors.initials: EB
authors.lastname: Moloney
authors.affiliation: Laboratory for Neuroregeneration, Netherlands Institute for Neuroscience, 1105 BA, Amsterdam, The Netherlands, and.
authors.forename: Joost
authors.initials: J
authors.lastname: Verhaagen
authors.affiliation: Department of Molecular Medicine, Max Planck Institute of Biochemistry, 82152 Martinsried, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Fässler
authors.affiliation: John van Geest Centre for Brain Repair, University of Cambridge, Cambridge CB2 0PY, United Kingdom, mra5@st-andrews.ac.uk jf108@cam.ac.uk.
authors.forename: James W
authors.initials: JW
authors.lastname: Fawcett
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology*; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002478:Cells, Cultured; D011508:Chondroitin Sulfate Proteoglycans / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D007839:Functional Laterality; D005727:Ganglia, Spinal / Q000166:cytology; D005786:Gene Expression Regulation / Q000502:physiology*; D016023:Integrins / Q000235:genetics / Q000378:metabolism*; D009416:Nerve Regeneration / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016501:Neurites / Q000502:physiology; D011312:Pressure; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000166:cytology*; D013119:Spinal Cord Injuries / Q000503:physiopathology*; D016138:Walking / Q000502:physiology
chemical_list: D011508:Chondroitin Sulfate Proteoglycans; C574034:Fermt1 protein, rat; D016023:Integrins; D009419:Nerve Tissue Proteins; D015740:Calcitonin Gene-Related Peptide
keywords: adeno-associated virus; alpha9 integrin; axon regeneration; dorsal root ganglion; kindlin-1; spinal cord