title: Sonic hedgehog and neurotrophin-3 increase oligodendrocyte numbers and myelination after spinal cord injury.
abstract: Spinal cord injury (SCI) results in loss of sensory and motor function below the level of injury and has limited available therapies. Multiple channel bridges have been investigated as a means to create a permissive environment for regeneration, with channels supporting axonal growth through the injury. Bridges support robust axon growth and myelination. Here, we investigated the cell types that myelinate axons in the bridges and whether over-expression of trophic factors can enhance myelination. Lentivirus encoding for neurotrophin-3 (NT3), sonic hedgehog (SHH) and the combination of these factors was delivered from bridges implanted into a lateral hemisection defect at T9/T10 in mice, and the response of endogenous progenitor cells within the spinal cord was investigated. Relative to control, the localized, sustained expression of these factors significantly increased growth of regenerating axons into the bridge and enhanced axon myelination 8 weeks after injury. SHH decreased the number of Sox2(+) cells and increased the number of Olig2(+) cells, whereas NT3 alone or in combination with SHH enhanced the numbers of GFAP(+) and Olig2(+) cells relative to control. For delivery of lentivirus encoding for either factor, we identified cells at various stages of differentiation along the oligodendrocyte lineage (e.g., O4(+), GalC(+)). Expression of NT3 enhanced myelination primarily by infiltrating Schwann cells, whereas SHH over-expression substantially increased myelination by oligodendrocytes. These studies further establish biomaterial-mediated gene delivery as a promising tool to direct activation and differentiation of endogenous progenitor cells for applications in regenerative medicine.
authors.affiliation: Department of Biomedical Engineering, McCormick School of Engineering, Northwestern University, Evanston, IL, USA.
authors.forename: Aline M
authors.initials: AM
authors.lastname: Thomas
authors.affiliation: Department of Chemical and Biological Engineering, McCormick School of Engineering, Northwestern University, Evanston, IL, USA.|Institute for BioNanotechnology in Medicine (IBNAM), Northwestern University, Chicago, IL, USA.
authors.forename: Stephanie K
authors.initials: SK
authors.lastname: Seidlits
authors.affiliation: Department of Chemical and Biological Engineering, McCormick School of Engineering, Northwestern University, Evanston, IL, USA.
authors.forename: Ashley G
authors.initials: AG
authors.lastname: Goodman
authors.affiliation: Department of Chemical and Biological Engineering, McCormick School of Engineering, Northwestern University, Evanston, IL, USA.
authors.forename: Todor V
authors.initials: TV
authors.lastname: Kukushliev
authors.affiliation: Department of Psychology, Weinberg College of Arts and Sciences, Northwestern University, Evanston, IL, USA.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Hassani
authors.affiliation: Department of Physical Medicine and Rehabilitation, University of California, Irvine, CA, USA.|Department of Anatomy and Neurobiology, University of California, Irvine, CA, USA.|Sue and Bill Gross Stem Cell Center, Irvine, CA, USA.|Institute for Memory Impairments and Neurological Disorders (MIND), Irvine, CA, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Cummings
authors.affiliation: Department of Physical Medicine and Rehabilitation, University of California, Irvine, CA, USA.|Department of Anatomy and Neurobiology, University of California, Irvine, CA, USA.|Sue and Bill Gross Stem Cell Center, Irvine, CA, USA.|Institute for Memory Impairments and Neurological Disorders (MIND), Irvine, CA, USA.
authors.forename: Aileen J
authors.initials: AJ
authors.lastname: Anderson
authors.affiliation: Department of Chemical and Biological Engineering, McCormick School of Engineering, Northwestern University, Evanston, IL, USA.|Institute for BioNanotechnology in Medicine (IBNAM), Northwestern University, Chicago, IL, USA.|Center for Reproductive Science (CRS), Northwestern University, Evanston, IL, USA.|Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA.|Chemistry of Life Processes Institute (CLP), Northwestern University, Evanston, IL, USA.
authors.forename: Lonnie D
authors.initials: LD
authors.lastname: Shea
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D005260:Female; D015316:Genetic Therapy / Q000379:methods / Q000592:standards; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D020933:Neurotrophin 3 / Q000235:genetics / Q000378:metabolism*; D009836:Oligodendroglia / Q000166:cytology / Q000378:metabolism*; D044968:Regenerative Medicine / Q000379:methods; D013119:Spinal Cord Injuries / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*
chemical_list: D053823:Hedgehog Proteins; D020933:Neurotrophin 3; C465570:Shh protein, mouse