title: White matter injury restoration after stem cell administration in subcortical ischemic stroke.
abstract: BACKGROUND
  Despite its high incidence, nerve fiber (axon and myelin) damage after cerebral infarct has not yet been extensively investigated. The aim of this study was to investigate white matter repair after adipose-derived mesenchymal stem cell (ADMSC) administration in an experimental model of subcortical stroke. Furthermore, we aimed to analyze the ADMSC secretome and whether this could be implicated in this repair function.
  
  
  METHODS
  An animal model of subcortical ischemic stroke with white matter affectation was induced in rats by injection of endothelin-1. At 24 hours, 2 × 10(6) ADMSC were administered intravenously to the treatment group. Functional evaluation, lesion size, fiber tract integrity, cell death, proliferation, white matter repair markers (Olig-2, NF, and MBP) and NogoA were all studied after sacrifice (7 days and 28 days). ADMSC migration and implantation in the brain as well as proteomics analysis and functions of the secretome were also analyzed.
  
  
  RESULTS
  Neither ADMSC migration nor implantation to the brain was observed after ADMSC administration. In contrast, ADMSC implantation was detected in peripheral organs. The treatment group showed a smaller functional deficit, smaller lesion area, less cell death, more oligodendrocyte proliferation, more white matter connectivity and higher amounts of myelin formation. The treated animals also showed higher levels of white matter-associated markers in the injured area than the control group. Proteomics analysis of the ADMSC secretome identified 2,416 proteins, not all of them previously described to be involved in brain plasticity.
  
  
  CONCLUSIONS
  White matter integrity in subcortical stroke is in part restored by ADMSC treatment; this is mediated by repair molecular factors implicated in axonal sprouting, remyelination and oligodendrogenesis. These findings are associated with improved functional recovery after stroke.
authors.affiliation: Department of Neurology and Stroke Center, Neuroscience and Cerebrovascular Research Laboratory, La Paz University Hospital, Neuroscience Area of IdiPAZ Health Research Institute, Autónoma University of Madrid, Paseo de la Castellana 261, 28046, Madrid, Spain. laura.otero@salud.madrid.org.
authors.forename: Laura
authors.initials: L
authors.lastname: Otero-Ortega
authors.affiliation: Department of Neurology and Stroke Center, Neuroscience and Cerebrovascular Research Laboratory, La Paz University Hospital, Neuroscience Area of IdiPAZ Health Research Institute, Autónoma University of Madrid, Paseo de la Castellana 261, 28046, Madrid, Spain. mgutierrezfernandez@salud.madrid.org.
authors.forename: María
authors.initials: M
authors.lastname: Gutiérrez-Fernández
authors.affiliation: Department of Neurology and Stroke Center, Neuroscience and Cerebrovascular Research Laboratory, La Paz University Hospital, Neuroscience Area of IdiPAZ Health Research Institute, Autónoma University of Madrid, Paseo de la Castellana 261, 28046, Madrid, Spain. Jaime.ramos@idipaz.es.
authors.forename: Jaime
authors.initials: J
authors.lastname: Ramos-Cejudo
authors.affiliation: Department of Neurology and Stroke Center, Neuroscience and Cerebrovascular Research Laboratory, La Paz University Hospital, Neuroscience Area of IdiPAZ Health Research Institute, Autónoma University of Madrid, Paseo de la Castellana 261, 28046, Madrid, Spain. berta.rodriguez@salud.madrid.org.
authors.forename: Berta
authors.initials: B
authors.lastname: Rodríguez-Frutos
authors.affiliation: Department of Neurology and Stroke Center, Neuroscience and Cerebrovascular Research Laboratory, La Paz University Hospital, Neuroscience Area of IdiPAZ Health Research Institute, Autónoma University of Madrid, Paseo de la Castellana 261, 28046, Madrid, Spain. blanca.fuentes@salud.madrid.org.
authors.forename: Blanca
authors.initials: B
authors.lastname: Fuentes
authors.affiliation: Department of Neurology, Clinical Neurosciences Research Laboratory, Hospital Clínico Universitario, Health Research Institute of Santiago de Compostela (IDIS), University of Santiago de Compostela, Travesía de Choupana, s/n, 15706, Santiago de Compostela, Spain. tomas.sobrino.moreiras@sergas.es.
authors.forename: Tomás
authors.initials: T
authors.lastname: Sobrino
authors.affiliation: Laboratory for Imaging and Spectroscopy by Magnetic Resonance (LISMAR), Institute of Biomedical Research Alberto Sols, CSIC-UAM, Arturo Duperier, 4, 28029, Madrid, Spain. tnavarro@iib.uam.es.
authors.forename: Teresa Navarro
authors.initials: TN
authors.lastname: Hernanz
authors.affiliation: Department of Neurology, Clinical Neurosciences Research Laboratory, Hospital Clínico Universitario, Health Research Institute of Santiago de Compostela (IDIS), University of Santiago de Compostela, Travesía de Choupana, s/n, 15706, Santiago de Compostela, Spain. francisco.campos.perez@sergas.es.
authors.forename: Francisco
authors.initials: F
authors.lastname: Campos
authors.affiliation: Cardiovascular Proteomics Laboratory & Proteomics Unit, Centro Nacional de Investigaciones Cardiovasculares, CNIC, Melchor Fernández, Almagro, 3, 28029, Madrid, Spain. jalopez@cnic.es.
authors.forename: Juan Antonio
authors.initials: JA
authors.lastname: López
authors.affiliation: Laboratory for Imaging and Spectroscopy by Magnetic Resonance (LISMAR), Institute of Biomedical Research Alberto Sols, CSIC-UAM, Arturo Duperier, 4, 28029, Madrid, Spain. scerdan@iib.uam.es.
authors.forename: Sebastián
authors.initials: S
authors.lastname: Cerdán
authors.affiliation: Cardiovascular Proteomics Laboratory & Proteomics Unit, Centro Nacional de Investigaciones Cardiovasculares, CNIC, Melchor Fernández, Almagro, 3, 28029, Madrid, Spain. jvazquez@cnic.es.
authors.forename: Jesús
authors.initials: J
authors.lastname: Vázquez
authors.affiliation: Department of Neurology and Stroke Center, Neuroscience and Cerebrovascular Research Laboratory, La Paz University Hospital, Neuroscience Area of IdiPAZ Health Research Institute, Autónoma University of Madrid, Paseo de la Castellana 261, 28046, Madrid, Spain. exuperio.diez@salud.madrid.org.
authors.forename: Exuperio
authors.initials: E
authors.lastname: Díez-Tejedor
mesh_terms: D000818:Animals; D017209:Apoptosis; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002454:Cell Differentiation; D002465:Cell Movement; D049109:Cell Proliferation; D056324:Diffusion Tensor Imaging; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000633:toxicity; D008279:Magnetic Resonance Imaging; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D004676:Myelin Basic Protein / Q000378:metabolism; D009185:Myelin Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D000070798:Nogo Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D009836:Oligodendroglia / Q000166:cytology / Q000378:metabolism; D020543:Proteome / Q000032:analysis; D040901:Proteomics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function; D020521:Stroke / Q000209:etiology / Q000628:therapy*; D066127:White Matter / Q000503:physiopathology*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D019332:Endothelin-1; D004676:Myelin Basic Protein; D009185:Myelin Proteins; D009419:Nerve Tissue Proteins; D000070798:Nogo Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D020543:Proteome; C522729:Olig2 protein, rat; C000603197:Rtn4 protein, rat