title: Neurosphere-derived cells exert a neuroprotective action by changing the ischemic microenvironment.
abstract: BACKGROUND
  Neurosphere-derived cells (NC), containing neural stem cells, various progenitors and more differentiated cells, were obtained from newborn C57/BL6 mice and infused in a murine model of focal ischemia with reperfusion to investigate if: 1) they decreased ischemic injury and restored brain function; 2) they induced changes in the environment in which they are infused; 3) changes in brain environment consequent to transient ischemia were relevant for NC action.
  
  
  RESULTS
  NC were infused intracerebroventricularly 4 h or 7 d after 30 min middle cerebral artery occlusion. In ischemic mice receiving cells at 4 h, impairment of open field performance was significantly improved and neuronal loss significantly reduced 7-14 d after ischemia compared to controls and to ischemic mice receiving cells at 7 d. Infusion of murine foetal fibroblast in the same experimental conditions was not effective. Assessment of infused cell distribution revealed that they migrated from the ventricle to the parenchyma, progressively decreased in number but they were observable up to 14 d. In mice receiving NC at 7 d and in sham-operated mice, few cells could be observed only at 24 h, indicating that the survival of these cells in brain tissue relates to the ischemic environment. The mRNA expression of trophic factors such as Insulin Growth Factor-1, Vascular Endothelial Growth Factor-A, Transforming Growth Factor-beta1, Brain Derived Neurotrophic Factor and Stromal Derived Factor-1alpha, as well as microglia/macrophage activation, increased 24 h after NC infusion in ischemic mice treated at 4 h compared to sham-operated and to mice receiving cells at 7 d.
  
  
  CONCLUSIONS
  NC reduce functional impairment and neuronal damage after ischemia/reperfusion injury. Several lines of evidence indicate that the reciprocal interaction between NC and the ischemic environment is crucial for NC protective actions. Based on these results we propose that a bystander control of the ischemic environment may be the mechanism used by NC to rapidly restore acutely injured brain function.
authors: Laboratory of Inflammation and Nervous System Diseases, Mario Negri Institute, Milano, Italy.
authors: Carmen
authors: C
authors: Capone
authors: Simona
authors: S
authors: Frigerio
authors: Stefano
authors: S
authors: Fumagalli
authors: Maurizio
authors: M
authors: Gelati
authors: Maria-Cristina
authors: MC
authors: Principato
authors: Claudio
authors: C
authors: Storini
authors: Mery
authors: M
authors: Montinaro
authors: Rudolf
authors: R
authors: Kraftsik
authors: Marco
authors: M
authors: De Curtis
authors: Eugenio
authors: E
authors: Parati
authors: Maria-Grazia
authors: MG
authors: De Simoni
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000473:pathology*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger