title: Combination of adipose-derived mesenchymal stem cells (ADMSC) and ADMSC-derived exosomes for protecting kidney from acute ischemia-reperfusion injury.
abstract: BACKGROUND
  In this study, we tested the hypothesis that a combined adipose-derived mesenchymal stem cell (ADMSC) and ADMSC-derived exosome therapy protected rat kidney from acute ischemia-reperfusion (IR) injury (i.e., ligation of both renal arteries for 1h and reperfusion for 72h prior to euthanization).
  
  
  RESULTS
  Adult-male SD rats (n=40) were equally categorized into group 1 (sham control), group 2 (IR), group 3 [IR+exosome (100μg)], group 4 [IR+ADMSC (1.2×10(6) cells)], and group 5 (IR-exosome-ADMSC). All therapies were performed at 3h after IR procedure from venous administration. By 72h, the creatinine level and kidney injury score were the lowest in group 1 and the highest in group 2, significantly higher in group 3 than in groups 4 and 5, and significantly higher in group 4 than in group 5 (all P<0.0001). The protein expression of inflammatory (TNF-α/NF-κB/IL-1β/MIF/PAI-1/Cox-2), oxidative-stress (NOX-1/NOX-2/oxidized protein), apoptotic (Bax/caspase-3/PARP), and fibrotic (Smad3/TGF-β) biomarkers showed an identical pattern, whereas the anti-apoptotic (Smad1/5, BMP-2) and angiogenesis (CD31/vWF/angiopoietin) biomarkers and mitochondrial cytochrome-C showed an opposite pattern of creatinine level among the five groups (all P<0.001). The microscopic findings of glomerular-damage (WT-1), renal tubular-damage (KIM-1), DNA-damage (γ-H2AX), inflammation (MPO/MIF/CD68) exhibited an identical pattern, whereas the podocyte components (podocin/p-cadherin/synaptopodin) displayed a reversed pattern of creatinine level (all P<0.0001).
  
  
  CONCLUSIONS
  Combined exosome-ADMSC therapy was superior to either one for protecting kidney from acute IR injury.
authors.affiliation: Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, 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 and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan; Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan; Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan; Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan; Department of Nursing, Asia University, Taichung 41354, Taiwan.
authors.forename: Hon-Kan
authors.initials: HK
authors.lastname: Yip
authors.affiliation: Department of Nursing, Asia University, Taichung 41354, Taiwan.
authors.forename: Pei-Lin
authors.initials: PL
authors.lastname: Shao
authors.affiliation: Orthopaedic Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Shun-Cheng
authors.initials: SC
authors.lastname: Wu
authors.affiliation: Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan.
authors.forename: Kuan-Hung
authors.initials: KH
authors.lastname: Chen
authors.affiliation: Division of Urology, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan.
authors.forename: Yen-Ta
authors.initials: YT
authors.lastname: Chen
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan.
authors.forename: Chih-Chao
authors.initials: CC
authors.lastname: Yang
authors.affiliation: Department of Emergency Medicine, E-Da Hospital, I-Shou University School of Medicine for International Students, Kaohsiung 82445, Taiwan.
authors.forename: Cheuk-Kwan
authors.initials: CK
authors.lastname: Sun
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan.
authors.forename: Gour-Shenq
authors.initials: GS
authors.lastname: Kao
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan.
authors.forename: Sheng-Yi
authors.initials: SY
authors.lastname: Chen
authors.affiliation: Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan.
authors.forename: Han-Tan
authors.initials: HT
authors.lastname: Chai
authors.affiliation: Division of Colorectal Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan.
authors.forename: Chia-Lo
authors.initials: CL
authors.lastname: Chang
authors.affiliation: Divisions of General Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan.
authors.forename: Chih-Hung
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Department of Orthopedics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine 83301, Kaohsiung, Taiwan. Electronic address: mellee@cgmh.org.tw.
authors.forename: Mel S
authors.initials: MS
authors.lastname: Lee
mesh_terms: D000273:Adipose Tissue / Q000166:cytology* / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism*; D001806:Blood Urea Nitrogen; D002478:Cells, Cultured; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D055354:Exosomes / Q000502:physiology*; D007674:Kidney Diseases / Q000378:metabolism / Q000628:therapy*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000628:therapy*
chemical_list: D015415:Biomarkers; D003404:Creatinine
keywords: Acute kidney ischemia–reperfusion injury; Adipose-derived mesenchymal stem cell; Exosome; Inflammation; Oxidative stress