title: Intra-carotid arterial administration of autologous peripheral blood-derived endothelial progenitor cells improves acute ischemic stroke neurological outcomes in rats.
abstract: OBJECTIVE
  We tested the hypothesis that transfusion of autologous peripheral blood-derived endothelial progenitor cells (PBDEPC) via the internal carotid artery could reduce brain-infarct zone (BIZ) and neurological deficit in rats following acute ischemic stroke (IS) induced by 50-min left middle cerebral artery occlusion.
  
  
  METHODS
  Adult male Sprague-Dawley rats (n=60) were equally divided into group 1 [sham control (SC)], group 2 [SC-PBDEPC (5.7 × 10(6)/kg)], group 3 (IS), group 4 [IS-low-dose PBDEPC (1.7 × 10(6)/kg)], group 5 [IS-high-dose PBDEPC (5.7×10(6)/kg)]. Groups 2 to 5 received G-CSF (35 μg/kg subcutaneously) for 4 days before drawing blood for PBDEPC culture.
  
  
  RESULTS
  By day 90, BIZ determined by histopathology (area) and brain MRI (volume) were highest in group 3, lowest in groups 1 and 2, higher in group 4 than in group 5 (all p<0.0001), and not significantly different between groups 1 and 2. Sensorimotor functional results exhibited an opposite pattern of BIZ among groups 3 to 5 (p<0.005). Angiogenesis biomarkers (SDF-1α, CXCR4, VEGF, angiopoietin-1) significantly increased progressively from groups 1 and 2 to group 5 (all p<0.0001). Oxidative-stress (NOX-1, NOX-2, oxidized protein), apoptotic (cleaved caspase 3 and PARP, mitochondrial Bax), inflammatory (MMP-9, TNF-α, AQP-4, GFAP, iNOS), and brain-damaged (cytosolic cytochrome-C) biomarkers showed an identical pattern, whereas anti-inflammatory (Bcl-2), mitochondrial preservation (mitochondrial cytochrome-C, PGC-1α), and endothelial function (CD31+, vWF+, eNOS) biomarkers, and vessel density showed an opposite pattern of BIZ among these five groups (all p<0.001).
  
  
  CONCLUSIONS
  Higher-dose was superior to lower-dose EPC treatment for reducing BIZ and improving neurological functional outcome.
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
authors.forename: Yung-Lung
authors.initials: YL
authors.lastname: Chen
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
authors.forename: Tzu-Hsien
authors.initials: TH
authors.lastname: Tsai
authors.affiliation: Department of Plastic Surgery, University Hospital of South Manchester, Manchester, UK.
authors.forename: Christopher Glenn
authors.initials: CG
authors.lastname: Wallace
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
authors.forename: Yi-Ling
authors.initials: YL
authors.lastname: Chen
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
authors.forename: Tien-Hung
authors.initials: TH
authors.lastname: Huang
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
authors.forename: Pei-Hsun
authors.initials: PH
authors.lastname: Sung
authors.affiliation: Division of Neurosurgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
authors.forename: Chun-Man
authors.initials: CM
authors.lastname: Yuen
authors.affiliation: Department of Emergency Medicine, Department of Medical Research, E-DA Hospital, I-Shou University, Kaohsiung, Taiwan.
authors.forename: Cheuk-Kwan
authors.initials: CK
authors.lastname: Sun
authors.affiliation: Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
authors.forename: Kun-Chen
authors.initials: KC
authors.lastname: Lin
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
authors.forename: Han-Tan
authors.initials: HT
authors.lastname: Chai
authors.affiliation: Division of thoracic and Cardiovascular Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
authors.forename: Jiunn-Jye
authors.initials: JJ
authors.lastname: Sheu
authors.affiliation: Division of thoracic and Cardiovascular Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
authors.forename: Fan-Yen
authors.initials: FY
authors.lastname: Lee
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan. Electronic address: han.gung@msa.hinet.net.
authors.forename: Hon-Kan
authors.initials: HK
authors.lastname: Yip
mesh_terms: D000208:Acute Disease; D000818:Animals; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D002339:Carotid Arteries; D002478:Cells, Cultured; D004195:Disease Models, Animal; D066026:Endothelial Progenitor Cells; D007269:Injections, Intra-Arterial; D008297:Male; D009422:Nervous System Diseases / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley
keywords: Acute ischemic stroke; Angiogenesis factors; Endothelial progenitor cells; Infarct volume; Oxidative stress