title: Osteopontin mediates survival, proliferation and migration of neural stem cells through the chemokine receptor CXCR4.
abstract: BACKGROUND
  Osteopontin (OPN) is a phosphoglycoprotein with important roles in tissue homeostasis, wound healing, immune regulation, and stress responses. It is expressed constitutively in the brain and upregulated during neuroinflammatory responses; for example, after focal cerebral ischemia. To date, its effects on neural stem cells (NSC) remain to be elucidated and are, accordingly, the subject of this study.
  
  
  METHODS
  Primary fetal rat NSC were cultured as homogenous monolayers and treated with different concentrations of OPN. Fundamental properties of NSC were assessed following OPN exposure, including proliferative activity, survival under oxidative stress, migration, and differentiation potential. To elucidate a putative action of OPN via the CXC chemokine receptor type 4 (CXCR4), the latter was blocked with AMD3100. To investigate effects of OPN on endogenous NSC in vivo, recombinant OPN was injected into the brain of healthy adult rats as well as rats subjected to focal cerebral ischemia. Effects of OPN on NSC proliferation and neurogenesis in the subventricular zone were studied immunohistochemically.
  
  
  RESULTS
  OPN dose-dependently increased the number of NSC in vitro. As hypothesized, this effect was mediated through CXCR4. The increase in NSC number was due to both enhanced cell proliferation and increased survival, and was confirmed in vivo. Additionally, OPN dose-dependently stimulated the migration of NSC via CXCR4. Moreover, in the presence of OPN, differentiation of NSC led to a significant increase in neurogenesis both in vitro as well as in vivo after cerebral ischemia.
  
  
  CONCLUSIONS
  Data show positive effects of OPN on survival, proliferation, migration, and neuronal differentiation of NSC. At least in part these effects were mediated via CXCR4. Results suggest that OPN is a promising substance for the targeted activation of NSC in future experimental therapies for neurological disorders such as stroke.
authors.affiliation: Department of Neurology, University Hospital of Cologne, Cologne, Germany. monika.rabenstein@uk-koeln.de.
authors.forename: Monika
authors.initials: M
authors.lastname: Rabenstein
authors.affiliation: Department of Neurology, University Hospital of Cologne, Cologne, Germany. joerg@germanynet.de.|Cognitive Neuroscience, Institute of Neuroscience and Medicine (INM-3), Research Centre Juelich, Leo-Brandt-Straße, 52425, Juelich, Germany. joerg@germanynet.de.
authors.forename: Joerg
authors.initials: J
authors.lastname: Hucklenbroich
authors.affiliation: Medical Imaging Physics, Institute of Neuroscience and Medicine (INM-4), Research Centre Juelich, Juelich, Germany. a.willuweit@fz-juelich.de.
authors.forename: Antje
authors.initials: A
authors.lastname: Willuweit
authors.affiliation: Department of Neurology, University Hospital of Cologne, Cologne, Germany. anne.ladwig@uk-koeln.de.
authors.forename: Anne
authors.initials: A
authors.lastname: Ladwig
authors.affiliation: Department of Neurology, University Hospital of Cologne, Cologne, Germany. G.R.Fink@fz-juelich.de.|Cognitive Neuroscience, Institute of Neuroscience and Medicine (INM-3), Research Centre Juelich, Leo-Brandt-Straße, 52425, Juelich, Germany. G.R.Fink@fz-juelich.de.
authors.forename: Gereon Rudolf
authors.initials: GR
authors.lastname: Fink
authors.affiliation: Department of Neurology, University Hospital of Cologne, Cologne, Germany. michael.schroeter@uk-koeln.de.|Cognitive Neuroscience, Institute of Neuroscience and Medicine (INM-3), Research Centre Juelich, Leo-Brandt-Straße, 52425, Juelich, Germany. michael.schroeter@uk-koeln.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Schroeter
authors.affiliation: Medical Imaging Physics, Institute of Neuroscience and Medicine (INM-4), Research Centre Juelich, Juelich, Germany. k.j.langen@fz-juelich.de.
authors.forename: Karl-Josef
authors.initials: KJ
authors.lastname: Langen
authors.affiliation: Department of Neurology, University Hospital of Cologne, Cologne, Germany. adele.rueger@uk-koeln.de.|Cognitive Neuroscience, Institute of Neuroscience and Medicine (INM-3), Research Centre Juelich, Leo-Brandt-Straße, 52425, Juelich, Germany. adele.rueger@uk-koeln.de.
authors.forename: Maria Adele
authors.initials: MA
authors.lastname: Rueger
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005333:Fetus / Q000166:cytology; D007150:Immunohistochemistry; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism*; D055495:Neurogenesis / Q000187:drug effects; D053495:Osteopontin / Q000494:pharmacology*; D051381:Rats; D019718:Receptors, CXCR4 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D019718:Receptors, CXCR4; D053495:Osteopontin