title: Intravenous administration of xenogenic adipose-derived mesenchymal stem cells (ADMSC) and ADMSC-derived exosomes markedly reduced brain infarct volume and preserved neurological function in rat after acute ischemic stroke.
abstract: We tested the hypothesis that combined xenogenic (from mini-pig) adipose-derived mesenchymal stem cell (ADMSC) and ADMSC-derived exosome therapy could reduce brain-infarct zone (BIZ) and enhance neurological recovery in rat after acute ischemic stroke (AIS) induced by 50-min left middle cerebral artery occlusion. Adult-male Sprague-Dawley rats (n = 60) were divided equally into group 1 (sham-control), group 2 (AIS), group 3 [AIS-ADMSC (1.2×106 cells)], group 4 [AIS-exosome (100μg)], and group 5 (AIS-exosome-ADMSC). All therapies were provided intravenously at 3h after AIS procedure. BIZ determined by histopathology (by day-60) and brain MRI (by day-28) were highest in group 2, lowest in group 1, higher in groups 3 and 4 than in group 5, but they showed no difference between groups 3 and 4 (all p < 0.0001). By day-28, sensorimotor functional results exhibited an opposite pattern to BIZ among the five groups (p < 0.005). Protein expressions of inflammatory (inducible nitric oxide synthase/tumor necrosis factor-α/nuclear factor-κB/interleukin-1β/matrix metalloproteinase-9/plasminogen activator inhibitor-1/RANTES), oxidative-stress (NOX-1/NOX-2/oxidized protein), apoptotic (caspase-3/ Poly-ADP-ribose polymerase), and fibrotic (Smad3/transforming growth factor-β) biomarkers, and cellular expressions of brain-damaged (γ-H2AX+/ XRCC1-CD90+/p53BP1-CD90+), inflammatory (CD11+/CD68+/glial fibrillary acid protein+) and brain-edema (aquaporin-4+) markers showed a similar pattern of BIZ among the groups (all n < 0.0001). In conclusion, xenogenic ADMSC/ADMSC-derived exosome therapy was safe and offered the additional benefit of reducing BIZ and improving neurological function in rat AIS.
authors: Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.|Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.
authors: Kuan-Hung
authors: KH
authors: Chen
authors: Department of Internal Medicine, Division of General Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors: Chih-Hung
authors: CH
authors: Chen
authors: Department of Plastic Surgery, University Hospital of South Manchester, Manchester, UK.
authors: Christopher Glenn
authors: CG
authors: Wallace
authors: Department of Surgery, Division of Neurosurgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors: Chun-Man
authors: CM
authors: Yuen
authors: Department of Internal Medicine, Division of Cardiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors: Gour-Shenq
authors: GS
authors: Kao
authors: Department of Internal Medicine, Division of Cardiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors: Yi-Ling
authors: YL
authors: Chen
authors: Department of Nursing, Asia University, Taichung, Taiwan.
authors: Pei-Lin
authors: PL
authors: Shao
authors: Department of Internal Medicine, Division of Cardiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors: Yung-Lung
authors: YL
authors: Chen
authors: Department of Internal Medicine, Division of Cardiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors: Han-Tan
authors: HT
authors: Chai
authors: Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors: Kun-Chen
authors: KC
authors: Lin
authors: Department of Emergency Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors: Chu-Feng
authors: CF
authors: Liu
authors: Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.
authors: Hsueh-Wen
authors: HW
authors: Chang
authors: Department of Orthopedics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors: Mel S
authors: MS
authors: Lee
authors: Department of Internal Medicine, Division of Cardiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.|Department of Nursing, Asia University, Taichung, Taiwan.|Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.|Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.|Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan.
authors: Hon-Kan
authors: HK
authors: Yip
mesh_terms: D000273:Adipose Tissue / Q000166:cytology*; D061605:Administration, Intravenous; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D055354:Exosomes / Q000378:metabolism*; D064593:Heterografts; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism*; D018384:Oxidative Stress; D051381:Rats; D020521:Stroke / Q000175:diagnosis / Q000209:etiology* / Q000378:metabolism* / Q000628:therapy; D016896:Treatment Outcome
keywords: Pathology Section; brain infarct size; exosomes; ischemic stroke; neurological function; xenogenic adipose-derived mesenchymal stem cell