title: NG2+ progenitors derived from embryonic stem cells penetrate glial scar and promote axonal outgrowth into white matter after spinal cord injury.
abstract: The glial scar resulting from spinal cord injury is rich in chondroitin sulfate proteoglycan (CSPG), a formidable barrier to axonal regeneration. We explored the possibility of breaching that barrier by first examining the scar in a functional in vitro model. We found that embryonic stem cell-derived neural lineage cells (ESNLCs) with prominent expression of nerve glial antigen 2 (NG2) survived, passed through an increasingly inhibitory gradient of CSPG, and expressed matrix metalloproteinase 9 (MMP-9) at the appropriate stage of their development. Outgrowth of axons from ESNLCs followed because the migrating cells sculpted pathways in which CSPG was degraded. The degradative mechanism involved MMP-9 but not MMP-2. To confirm these results in vivo, we transplanted ESNLCs directly into the cavity of a contused spinal cord 9 days after injury. A week later, ESNLCs survived and were expressing both NG2 and MMP-9. Their axons had grown through long distances (>10 mm), although they preferred to traverse white rather than gray matter. These data are consistent with the concept that expression of inhibitory CSPG within the injury scar is an important impediment to regeneration but that NG2+ progenitors derived from ESNLCs can modify the microenvironment to allow axons to grow through the barrier. This beneficial action may be partly due to developmental expression of MMP-9. We conclude that it might eventually be possible to encourage axonal regeneration in the human spinal cord by transplanting ESNLCs or other cells that express NG2.
authors.affiliation: The International Center for Spinal Cord Injury, Hugo W. Moser Research Institute at the Kennedy Krieger Institute, Baltimore, Maryland, USA; Department of Neurosurgery, Washington University School of Medicine, St. Louis, Missouri, USA; Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA; Department of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Sudhakar.Vadivelu@cchmc.org.
authors.forename: Sudhakar
authors.initials: S
authors.lastname: Vadivelu
authors.affiliation: The International Center for Spinal Cord Injury, Hugo W. Moser Research Institute at the Kennedy Krieger Institute, Baltimore, Maryland, USA; Department of Neurosurgery, Washington University School of Medicine, St. Louis, Missouri, USA; Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA; Department of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Todd J
authors.initials: TJ
authors.lastname: Stewart
authors.affiliation: The International Center for Spinal Cord Injury, Hugo W. Moser Research Institute at the Kennedy Krieger Institute, Baltimore, Maryland, USA; Department of Neurosurgery, Washington University School of Medicine, St. Louis, Missouri, USA; Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA; Department of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Qu
authors.affiliation: The International Center for Spinal Cord Injury, Hugo W. Moser Research Institute at the Kennedy Krieger Institute, Baltimore, Maryland, USA; Department of Neurosurgery, Washington University School of Medicine, St. Louis, Missouri, USA; Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA; Department of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Horn
authors.affiliation: The International Center for Spinal Cord Injury, Hugo W. Moser Research Institute at the Kennedy Krieger Institute, Baltimore, Maryland, USA; Department of Neurosurgery, Washington University School of Medicine, St. Louis, Missouri, USA; Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA; Department of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Su
authors.initials: S
authors.lastname: Liu
authors.affiliation: The International Center for Spinal Cord Injury, Hugo W. Moser Research Institute at the Kennedy Krieger Institute, Baltimore, Maryland, USA; Department of Neurosurgery, Washington University School of Medicine, St. Louis, Missouri, USA; Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA; Department of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Qun
authors.initials: Q
authors.lastname: Li
authors.affiliation: The International Center for Spinal Cord Injury, Hugo W. Moser Research Institute at the Kennedy Krieger Institute, Baltimore, Maryland, USA; Department of Neurosurgery, Washington University School of Medicine, St. Louis, Missouri, USA; Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA; Department of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Jerry
authors.initials: J
authors.lastname: Silver
authors.affiliation: The International Center for Spinal Cord Injury, Hugo W. Moser Research Institute at the Kennedy Krieger Institute, Baltimore, Maryland, USA; Department of Neurosurgery, Washington University School of Medicine, St. Louis, Missouri, USA; Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA; Department of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: McDonald
mesh_terms: D000941:Antigens / Q000378:metabolism; D001369:Axons / Q000378:metabolism; D011508:Chondroitin Sulfate Proteoglycans / Q000378:metabolism; D002921:Cicatrix / Q000378:metabolism / Q000473:pathology; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism / Q000637:transplantation; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009416:Nerve Regeneration; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D011509:Proteoglycans / Q000378:metabolism; D013119:Spinal Cord Injuries / Q000473:pathology / Q000628:therapy*; D066127:White Matter / Q000254:growth & development* / Q000378:metabolism; D000099216:Chondroitin Sulfate Proteoglycan 4
chemical_list: D000941:Antigens; D011508:Chondroitin Sulfate Proteoglycans; D020780:Matrix Metalloproteinase 9; D011509:Proteoglycans; D000099216:Chondroitin Sulfate Proteoglycan 4; C579270:MMP9 protein, human
keywords: Axonal regeneration; Central nervous system; Differentiation; Glia; Glial scar; Matrix metalloproteinase; Neural progenitor; Plasticity; Spinal cord injury