title: Synergistic Effects of Transplanted Endothelial Progenitor Cells and RWJ 67657 in Diabetic Ischemic Stroke Models.
abstract: OBJECTIVE
  An immature vascular phenotype in diabetes mellitus may cause more severe vascular damage and poorer functional outcomes after stroke, and it would be feasible to repair damaged functional vessels using endothelial progenitor cell (EPC) transplantation. However, high glucose induces p38 mitogen-activated protein kinase activation, which can accelerate the senescence and apoptosis of EPCs. The aim of this study was to investigate the combined effects of EPC transplantation and p38 mitogen-activated protein kinase inhibitor administration on diabetic stroke outcomes.
  
  
  METHODS
  Bone marrow-derived EPCs were injected intra-arterially into db/db mice after ischemic stroke induction. RWJ 67657 (RWJ), a p38 mitogen-activated protein kinase inhibitor, was administered orally for 7 consecutive days, with the first dose given 30 minutes before stroke induction. Functional outcome was determined at days 0, 1, 7, 14, and 21. Angiogenesis, neurogenesis, infarct volume, and Western blotting assays were performed on day 7, and white matter remodeling was determined on day 14.
  
  
  RESULTS
  Neither EPC transplantation nor RWJ administration alone significantly improved diabetic stroke outcome although RWJ displayed a potent anti-inflammatory effect. By both improving the functioning of EPCs and reducing inflammation, EPC transplantation plus RWJ administration in vivo synergistically promoted angiogenesis and neurogenesis after diabetic stroke. In addition, the white matter remodeling, behavioral scores, and expressions of vascular endothelial growth factor and brain-derived neurotrophic factor were significantly increased in diabetic mice treated with both EPCs and RWJ.
  
  
  CONCLUSIONS
  The combination of EPC transplantation and RWJ administration accelerated recovery from diabetic stroke, which might have been caused by increased levels of proangiogenic and neurotrophic factors.
authors.affiliation: From the Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School (Y.-Y.B., D.C., Z.Z., C.-Q.L., S.J.) and Department of General Surgery, Zhongda Hospital, School of Medicine (L.W.), Southeast University, Nanjing, China; and Department of Clinical Infection, Microbiology and Immunology, Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom (G.W.).
authors.forename: Ying-Ying
authors.initials: YY
authors.lastname: Bai
authors.affiliation: From the Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School (Y.-Y.B., D.C., Z.Z., C.-Q.L., S.J.) and Department of General Surgery, Zhongda Hospital, School of Medicine (L.W.), Southeast University, Nanjing, China; and Department of Clinical Infection, Microbiology and Immunology, Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom (G.W.).
authors.forename: Lishan
authors.initials: L
authors.lastname: Wang
authors.affiliation: From the Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School (Y.-Y.B., D.C., Z.Z., C.-Q.L., S.J.) and Department of General Surgery, Zhongda Hospital, School of Medicine (L.W.), Southeast University, Nanjing, China; and Department of Clinical Infection, Microbiology and Immunology, Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom (G.W.).
authors.forename: Di
authors.initials: D
authors.lastname: Chang
authors.affiliation: From the Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School (Y.-Y.B., D.C., Z.Z., C.-Q.L., S.J.) and Department of General Surgery, Zhongda Hospital, School of Medicine (L.W.), Southeast University, Nanjing, China; and Department of Clinical Infection, Microbiology and Immunology, Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom (G.W.).
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: From the Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School (Y.-Y.B., D.C., Z.Z., C.-Q.L., S.J.) and Department of General Surgery, Zhongda Hospital, School of Medicine (L.W.), Southeast University, Nanjing, China; and Department of Clinical Infection, Microbiology and Immunology, Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom (G.W.).
authors.forename: Chun-Qiang
authors.initials: CQ
authors.lastname: Lu
authors.affiliation: From the Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School (Y.-Y.B., D.C., Z.Z., C.-Q.L., S.J.) and Department of General Surgery, Zhongda Hospital, School of Medicine (L.W.), Southeast University, Nanjing, China; and Department of Clinical Infection, Microbiology and Immunology, Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom (G.W.).
authors.forename: Guozheng
authors.initials: G
authors.lastname: Wang
authors.affiliation: From the Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School (Y.-Y.B., D.C., Z.Z., C.-Q.L., S.J.) and Department of General Surgery, Zhongda Hospital, School of Medicine (L.W.), Southeast University, Nanjing, China; and Department of Clinical Infection, Microbiology and Immunology, Institute of Infection and Global Health, University of Liverpool, Liverpool, United Kingdom (G.W.). jsh0836@hotmail.com.
authors.forename: Shenghong
authors.initials: S
authors.lastname: Ju
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000473:pathology / Q000628:therapy*; D003921:Diabetes Mellitus, Experimental / Q000473:pathology / Q000628:therapy*; D004195:Disease Models, Animal; D066026:Endothelial Progenitor Cells / Q000637:transplantation*; D007093:Imidazoles / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000008:administration & dosage*; D033581:Stem Cell Transplantation / Q000379:methods*; D020521:Stroke / Q000473:pathology / Q000628:therapy*; D016896:Treatment Outcome
chemical_list: D007093:Imidazoles; D011725:Pyridines; C400277:RWJ 67657; D020928:Mitogen-Activated Protein Kinases
keywords: cell transplantation; diabetes mellitus; endothelial progenitor cells; inflammation; p38 mitogen-activated protein kinases