title: Endothelial progenitor cells and neural progenitor cells synergistically protect cerebral endothelial cells from Hypoxia/reoxygenation-induced injury via activating the PI3K/Akt pathway.
abstract: BACKGROUND
  Protection of cerebral endothelial cells (ECs) from hypoxia/reoxygenation (H/R)-induced injury is an important strategy for treating ischemic stroke. In this study, we investigated whether co-culture with endothelial progenitor cells (EPCs) and neural progenitor cells (NPCs) synergistically protects cerebral ECs against H/R injury and the underlying mechanism.
  
  
  RESULTS
  EPCs and NPCs were respectively generated from inducible pluripotent stem cells. Human brain ECs were used to produce an in vitro H/R-injury model. Data showed: 1) Co-culture with EPCs and NPCs synergistically inhibited H/R-induced reactive oxygen species (ROS) over-production, apoptosis, and improved the angiogenic and barrier functions (tube formation and permeability) in H/R-injured ECs. 2) Co-culture with NPCs up-regulated the expression of vascular endothelial growth factor receptor 2 (VEGFR2). 3) Co-culture with EPCs and NPCs complementarily increased vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF) levels in conditioned medium, and synergistically up-regulated the expression of p-Akt/Akt and p-Flk1/VEGFR2 in H/R-injured ECs. 4) Those effects could be decreased or abolished by inhibition of both VEGFR2 and tyrosine kinase B (TrkB) or phosphatidylinositol-3-kinase (PI3K).
  
  
  CONCLUSIONS
  Our data demonstrate that EPCs and NPCs synergistically protect cerebral ECs from H/R-injury, via activating the PI3K/Akt pathway which mainly depends on VEGF and BDNF paracrine.
authors: Department of Pharmacology & Toxicology, Boonshoft School of Medicine, Wright State University, 3640 Colonel Glenn Hwy, Dayton, OH, 45435, USA. wang.140@wright.edu.
authors: Jinju
authors: J
authors: Wang
authors: Department of Neurology, Affiliated Hospital of Guangdong Medical College, Zhanjiang, 524001, Guangdong, China. chenyusen925@yahoo.com.cn.
authors: Yusen
authors: Y
authors: Chen
authors: Wuhan Institute of Physical Education, College of Health Science, Wuhan, 430079, Hubei, China. yangyi999999@yahoo.com.
authors: Yi
authors: Y
authors: Yang
authors: Department of Pharmacology & Toxicology, Boonshoft School of Medicine, Wright State University, 3640 Colonel Glenn Hwy, Dayton, OH, 45435, USA. xiao.13@wright.edu.
authors: Xiang
authors: X
authors: Xiao
authors: Department of Pharmacology & Toxicology, Boonshoft School of Medicine, Wright State University, 3640 Colonel Glenn Hwy, Dayton, OH, 45435, USA. shuzhen.chen@wright.edu.
authors: Shuzhen
authors: S
authors: Chen
authors: Department of Pharmacology & Toxicology, Boonshoft School of Medicine, Wright State University, 3640 Colonel Glenn Hwy, Dayton, OH, 45435, USA. cheng.zhang@wright.edu.
authors: Cheng
authors: C
authors: Zhang
authors: Department of Neurology, Wright State University, 3640 Colonel Glenn Hwy, Dayton, 45435, Ohio, USA. Bradley.jacobs@wright.edu.
authors: Bradley
authors: B
authors: Jacobs
authors: Department of Neurology, Affiliated Hospital of Guangdong Medical College, Zhanjiang, 524001, Guangdong, China. binzhaoe@163.com.
authors: Bin
authors: B
authors: Zhao
authors: Department of Pharmacology & Toxicology, Boonshoft School of Medicine, Wright State University, 3640 Colonel Glenn Hwy, Dayton, OH, 45435, USA. ji.bihl@wright.edu.
authors: Ji
authors: J
authors: Bihl
authors: Department of Pharmacology & Toxicology, Boonshoft School of Medicine, Wright State University, 3640 Colonel Glenn Hwy, Dayton, OH, 45435, USA. yanfang.chen@wright.edu.|Department of Neurology, Affiliated Hospital of Guangdong Medical College, Zhanjiang, 524001, Guangdong, China. yanfang.chen@wright.edu.|Department of Neurology, Wright State University, 3640 Colonel Glenn Hwy, Dayton, 45435, Ohio, USA. yanfang.chen@wright.edu.|Department of Internal Medicine, Wright State University, 3640 Colonel Glenn Hwy, Dayton, 45435, Ohio, USA. yanfang.chen@wright.edu.
authors: Yanfang
authors: Y
authors: Chen
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D054022:Cerebrum / Q000473:pathology*; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000494:pharmacology; D066026:Endothelial Progenitor Cells / Q000378:metabolism*; D006801:Humans; D000860:Hypoxia / Q000473:pathology*; D057026:Induced Pluripotent Stem Cells / Q000166:cytology; D008954:Models, Biological; D018919:Neovascularization, Physiologic / Q000187:drug effects; D058953:Neural Stem Cells / Q000378:metabolism*; D000066829:Neuroprotection; D018696:Neuroprotective Agents / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010100:Oxygen / Q000494:pharmacology*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D017077:Culture Media, Conditioned; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D042461:Vascular Endothelial Growth Factor A; D058539:Phosphatidylinositol 3-Kinase; D040301:Vascular Endothelial Growth Factor Receptor-2; D051057:Proto-Oncogene Proteins c-akt; D010100:Oxygen