title: Genetically modified mesenchymal stem cells (MSCs) promote axonal regeneration and prevent hypersensitivity after spinal cord injury.
abstract: Neurotrophins and the transplantation of bone marrow-derived stromal cells (MSCs) are both candidate therapies targeting spinal cord injury (SCI). While some studies have suggested the ability of MSCs to transdifferentiate into neural cells, other SCI studies have proposed anti-inflammatory and other mechanisms underlying established beneficial effects. We grafted rat MSCs genetically modified to express MNTS1, a multineurotrophin that binds TrkA, TrkB and TrkC, and p75(NTR) receptors or MSC-MNTS1/p75(-) that binds mainly to the Trk receptors. Seven days after contusive SCI, PBS-only, GFP-MSC, MSC-MNTS1/GFP or MSC-MNTS1/p75(-)/GFP were delivered into the injury epicenter. All transplanted groups showed reduced inflammation and cystic cavity size compared to control SCI rats. Interestingly, transplantation of the MSC-MNTS1 and MSC-MNTS1/p75(-), but not the naïve MSCs, enhanced axonal growth and significantly prevented cutaneous hypersensitivity after SCI. Moreover, transplantation of MSC-MNTS1/p75(-) promoted angiogenesis and modified glial scar formation. These findings suggest that MSCs transduced with a multineurotrophin are effective in promoting cell growth and improving sensory function after SCI. These novel data also provide insight into the neurotrophin-receptor dependent mechanisms through which cellular transplantation leads to functional improvement after experimental SCI.
authors.affiliation: Department of Neurological Surgery, The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL, USA; Department of Orthopedic Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Gentaro
authors.initials: G
authors.lastname: Kumagai
authors.forename: Pantelis
authors.initials: P
authors.lastname: Tsoulfas
authors.forename: Satoshi
authors.initials: S
authors.lastname: Toh
authors.forename: Ian
authors.initials: I
authors.lastname: McNiece
authors.forename: Helen M
authors.initials: HM
authors.lastname: Bramlett
authors.forename: W Dalton
authors.initials: WD
authors.lastname: Dietrich
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism*; D006967:Hypersensitivity / Q000378:metabolism / Q000503:physiopathology / Q000601:surgery; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells; D009414:Nerve Growth Factors / Q000378:metabolism*; D009416:Nerve Regeneration / Q000235:genetics*; D009474:Neurons / Q000378:metabolism; D051381:Rats; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*; D020127:Recovery of Function / Q000502:physiology; D013116:Spinal Cord / Q000378:metabolism / Q000601:surgery; D013119:Spinal Cord Injuries / Q000378:metabolism / Q000503:physiopathology / Q000601:surgery*
chemical_list: D009414:Nerve Growth Factors; D017475:Receptors, Nerve Growth Factor
keywords: Axonal regeneration; Functional recovery; MNTS1; Rat bone marrow stromal cells; Spinal cord injury; Transplantation; Viral vector transduction; p75