title: Diffuse and persistent blood-spinal cord barrier disruption after contusive spinal cord injury rapidly recovers following intravenous infusion of bone marrow mesenchymal stem cells.
abstract: Intravenous infusion of mesenchymal stem cells (MSCs) has been shown to reduce the severity of experimental spinal cord injury (SCI), but mechanisms are not fully understood. One important consequence of SCI is damage to the microvasculature and disruption of the blood spinal cord barrier (BSCB). In the present study we induced a contusive SCI at T9 in the rat and studied the effects of intravenous MSC infusion on BSCB permeability, microvascular architecture and locomotor recovery over a 10week period. Intravenously delivered MSCs could not be identified in the spinal cord, but distributed primarily to the lungs where they survived for a couple of days. Spatial and temporal changes in BSCB integrity were assessed by intravenous infusions of Evans blue (EvB) with in vivo and ex vivo optical imaging and spectrophotometric quantitation of EvB leakage into the parenchyma. SCI resulted in prolonged BSCB leakage that was most severe at the impact site but disseminated extensively rostral and caudal to the lesion over 6weeks. Contused spinal cords also showed an increase in vessel size, reduced vessel number, dissociation of pericytes from microvessels and decreases in von Willebrand factor (vWF) and endothelial barrier antigen (EBA) expression. In MSC-treated rats, BSCB leakage was reduced, vWF expression was increased and locomotor function improved beginning 1 week post-MSC infusion, i.e., 2weeks post-SCI. These results suggest that intravenously delivered MSCs have important effects on reducing BSCB leakage which could contribute to their therapeutic efficacy.
authors.affiliation: Department of Neurology, Yale University School of Medicine, VA Connecticut Healthcare System, West Haven, CT 06516, USA; Center for Neuroscience Regeneration Research, VA Connecticut Healthcare System, West Haven, CT 06516, USA; Department of Neural Regenerative Medicine, Research Institute for Frontier Medicine, Sapporo Medical University, Sapporo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Matsushita
authors.affiliation: Department of Neurology, Yale University School of Medicine, VA Connecticut Healthcare System, West Haven, CT 06516, USA; Center for Neuroscience Regeneration Research, VA Connecticut Healthcare System, West Haven, CT 06516, USA.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Lankford
authors.affiliation: Department of Neurology, Yale University School of Medicine, VA Connecticut Healthcare System, West Haven, CT 06516, USA; Center for Neuroscience Regeneration Research, VA Connecticut Healthcare System, West Haven, CT 06516, USA.
authors.forename: Edgardo J
authors.initials: EJ
authors.lastname: Arroyo
authors.affiliation: Department of Neurology, Yale University School of Medicine, VA Connecticut Healthcare System, West Haven, CT 06516, USA; Center for Neuroscience Regeneration Research, VA Connecticut Healthcare System, West Haven, CT 06516, USA; Department of Neural Regenerative Medicine, Research Institute for Frontier Medicine, Sapporo Medical University, Sapporo, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Sasaki
authors.affiliation: Department of Neurology, Yale University School of Medicine, VA Connecticut Healthcare System, West Haven, CT 06516, USA; Center for Neuroscience Regeneration Research, VA Connecticut Healthcare System, West Haven, CT 06516, USA; Department of Plastic, Hand, and Reconstructive Surgery, Hannover Medical School, Hannover, Germany.
authors.forename: Milad
authors.initials: M
authors.lastname: Neyazi
authors.affiliation: Department of Neurology, Yale University School of Medicine, VA Connecticut Healthcare System, West Haven, CT 06516, USA; Center for Neuroscience Regeneration Research, VA Connecticut Healthcare System, West Haven, CT 06516, USA; Department of Plastic, Hand, and Reconstructive Surgery, Hannover Medical School, Hannover, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Radtke
authors.affiliation: Department of Neurology, Yale University School of Medicine, VA Connecticut Healthcare System, West Haven, CT 06516, USA; Center for Neuroscience Regeneration Research, VA Connecticut Healthcare System, West Haven, CT 06516, USA. Electronic address: jeffery.kocsis@yale.edu.
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Kocsis
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000503:physiopathology*; D064987:Cell- and Tissue-Based Therapy; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000473:pathology; D005106:Exploratory Behavior; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D008124:Locomotion / Q000502:physiology; D008297:Male; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D055806:Microvessels / Q000473:pathology; D010539:Permeability; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D013119:Spinal Cord Injuries / Q000473:pathology* / Q000628:therapy*; D013997:Time Factors; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D000954:Antigens, Surface; D005904:Glial Fibrillary Acidic Protein; C114781:endothelial barrier antigen, rat; D014841:von Willebrand Factor; D020797:Receptor, Platelet-Derived Growth Factor beta
keywords: Blood spinal cord barrier; Mesenchymal stem cell; Pericytes; Spinal cord injury