title: Neuroinflammatory signals enhance the immunomodulatory and neuroprotective properties of multipotent adult progenitor cells.
abstract: BACKGROUND
  Stem cell-based therapies are currently widely explored as a tool to treat neuroimmune diseases. Multipotent adult progenitor cells (MAPC) have been suggested to have strong immunomodulatory and neuroprotective properties in several experimental models. In this study, we investigate whether MAPC are of therapeutic interest for neuroinflammatory disorders such as multiple sclerosis by evaluating their capacities to modulate crucial pathological features and gain insights into the molecular pathways involved.
  
  
  METHODS
  Rat MAPC were treated with combinations of pro-inflammatory cytokines that are closely associated with neuroinflammatory conditions, a process called licensing. mRNA expression of immunomodulatory molecules, chemokines and chemokine receptors was investigated. The migratory potential of licensed rat MAPC towards a broad spectrum of chemokines was tested in a Transwell assay. Furthermore, the effect of licensing on the ability of rat MAPC to attract and suppress the proliferation of encephalitogenic T cells was assessed. Finally, neuroprotective properties of rat MAPC were determined in the context of protection from oxidative stress of oligodendrocytes. Therefore, rat MAPC were incubated with conditioned medium of OLN93 cells subjected to sublethal doses of hydrogen peroxide and the gene expression of neurotrophic factors was assessed.
  
  
  RESULTS
  After licensing, a wide variety of immunomodulatory molecules and chemokines, including inducible nitric oxide synthase and fractalkine, were upregulated by rat MAPC. The migratory properties of rat MAPC towards various chemokines were also altered. In addition, rat MAPC were found to inhibit antigen-specific T-cell proliferation and this suppressive effect was further enhanced after pro-inflammatory treatment. This phenomenon was partially mediated through inducible nitric oxide synthase or cyclooxygenase-2. Activated rat MAPC secreted factors that led to attraction of myelin-specific T cells. Finally, exposure of rat MAPC to an in vitro simulated neurodegenerative environment induced the upregulation of mRNA levels of vascular endothelial growth factor and ciliary neurotrophic factor. Factors secreted by rat MAPC in response to this environment partially protected OLN93 cells from hydrogen peroxide-induced cell death.
  
  
  CONCLUSIONS
  Rat MAPC possess immune modulatory and neuroprotective properties which are enhanced in response to neuroinflammatory signals. These findings thereby warrant further research to evaluate MAPC transplantation as a therapeutic approach in diseases with an immunological and neurodegenerative component such as multiple sclerosis.
authors.affiliation: Hasselt University, Biomedical Research Institute/Transnational University Limburg, School of Life Sciences, Campus Diepenbeek, Agoralaan building C, 3590, Diepenbeek, Belgium. stelios.ravanidis@uhasselt.be.
authors.forename: Stylianos
authors.initials: S
authors.lastname: Ravanidis
authors.affiliation: Hasselt University, Biomedical Research Institute/Transnational University Limburg, School of Life Sciences, Campus Diepenbeek, Agoralaan building C, 3590, Diepenbeek, Belgium. jeroen.bogie@uhasselt.be.
authors.forename: Jeroen F J
authors.initials: JF
authors.lastname: Bogie
authors.affiliation: Hasselt University, Biomedical Research Institute/Transnational University Limburg, School of Life Sciences, Campus Diepenbeek, Agoralaan building C, 3590, Diepenbeek, Belgium. raf.donders@uhasselt.be.
authors.forename: Raf
authors.initials: R
authors.lastname: Donders
authors.affiliation: ReGenesys BVBA, Leuven, Belgium. dcraeye@regenesys.eu.
authors.forename: David
authors.initials: D
authors.lastname: Craeye
authors.affiliation: Department of Regenerative Medicine, Athersys Inc., Cleveland, OH, USA. rwmays@athersys.com.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Mays
authors.affiliation: Department of Regenerative Medicine, Athersys Inc., Cleveland, OH, USA. rdeans@athersys.com.
authors.forename: Robert
authors.initials: R
authors.lastname: Deans
authors.affiliation: ReGenesys BVBA, Leuven, Belgium. kgijbels@regenesys.eu.
authors.forename: Kristel
authors.initials: K
authors.lastname: Gijbels
authors.affiliation: Hasselt University, Biomedical Research Institute/Transnational University Limburg, School of Life Sciences, Campus Diepenbeek, Agoralaan building C, 3590, Diepenbeek, Belgium. annelies.bronckaers@uhasselt.be.
authors.forename: Annelies
authors.initials: A
authors.lastname: Bronckaers
authors.affiliation: Hasselt University, Biomedical Research Institute/Transnational University Limburg, School of Life Sciences, Campus Diepenbeek, Agoralaan building C, 3590, Diepenbeek, Belgium. piet.stinissen@uhasselt.be.
authors.forename: Piet
authors.initials: P
authors.lastname: Stinissen
authors.affiliation: ReGenesys BVBA, Leuven, Belgium. jpinxteren@regenesys.eu.
authors.forename: Jef
authors.initials: J
authors.lastname: Pinxteren
authors.affiliation: Hasselt University, Biomedical Research Institute/Transnational University Limburg, School of Life Sciences, Campus Diepenbeek, Agoralaan building C, 3590, Diepenbeek, Belgium. niels.hellings@uhasselt.be.
authors.forename: Niels
authors.initials: N
authors.lastname: Hellings
mesh_terms: D053687:Adult Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D000818:Animals; D002460:Cell Line; D002465:Cell Movement; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016207:Cytokines / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D009836:Oligodendroglia / Q000378:metabolism; D018384:Oxidative Stress; D039904:Pluripotent Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D051381:Rats; D011917:Rats, Inbred Lew
chemical_list: D017077:Culture Media, Conditioned; D016207:Cytokines; D018696:Neuroprotective Agents