title: Mesenchymal stem cells maintain blood-brain barrier integrity by inhibiting aquaporin-4 upregulation after cerebral ischemia.
abstract: BACKGROUND
  Cerebral ischemia upregulates aquaporin-4 expression, increases blood-brain barrier (BBB) permeability, and induces brain edema. Mesenchymal stem cells (MSCs) can repress inflammatory cytokines and show great potential for ischemic stroke therapy. However, the effect of MSCs regarding the protection of ischemia-induced BBB break down is unknown.
  
  
  OBJECTIVE
  We test whether MSCs therapy protects BBB integrity and explore the molecular mechanisms of aquaporin-4 on BBB integrity.
  
  
  RESULTS
  Two hundred and twenty-eight adult CD1 male mice underwent 90 minutes transient middle cerebral artery occlusion and received 2 × 10(5) MSCs intracranial transplantation. The neurological severity score was improved and both ischemia-induced brain edema and BBB leakage were reduced in MSC-treated mice. MSCs therapy reduced astrocyte apoptosis and inhibited ischemia-induced aquaporin-4 upregulation. In addition, small-interfering RNA knockdown of aquaporin-4 after cerebral ischemia effectively reduced aquaporin-4 expression, brain edema, BBB leakage, and astrocyte apoptosis. Conditional medium from lipopolysaccharide (LPS)-activated microglia enhanced aquaporin-4 expression, p38 and JNK phosphorylation, and apoptosis of cultured astrocytes. MSC treatment reduced the expression of inflammatory cytokines in LPS-activated microglia, and subsequently reduced aquaporin-4 expression and apoptosis of astrocytes. Knockdown of aquaporin-4 in cultured astrocytes also reduced apoptosis. Treatment with p38 and JNK inhibitors showed that p38, but not the JNK signaling pathway, was responsible for the aquaporin-4 upregulation.
  
  
  CONCLUSIONS
  MSCs protected BBB integrity by reducing the apoptosis of astrocytes after ischemic attack, which was due to the attenuation of inflammatory response and downregulation of aquaporin-4 expression via p38 signaling pathway.
authors.affiliation: Neuroscience and Neuroengineering Research Center, Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, People's Republic of China.
authors.forename: Guanghui
authors.initials: G
authors.lastname: Tang
authors.forename: Yanqun
authors.initials: Y
authors.lastname: Liu
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Zhang
authors.forename: Yifan
authors.initials: Y
authors.lastname: Lu
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.forename: Jun
authors.initials: J
authors.lastname: Huang
authors.forename: Yaning
authors.initials: Y
authors.lastname: Li
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Chen
authors.forename: Xiang
authors.initials: X
authors.lastname: Gu
authors.forename: Yongting
authors.initials: Y
authors.lastname: Wang
authors.forename: Guo-Yuan
authors.initials: GY
authors.lastname: Yang
mesh_terms: D000818:Animals; D051401:Aquaporin 4 / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000378:metabolism* / Q000473:pathology; D001929:Brain Edema / Q000378:metabolism; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology; D002544:Cerebral Infarction / Q000378:metabolism; D004195:Disease Models, Animal; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D015398:Signal Transduction / Q000502:physiology; D020521:Stroke / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C496031:Aqp4 protein, mouse; D051401:Aquaporin 4
keywords: Aquaporin-4; Blood-brain barrier; Edema; Inflammation; Ischemia