title: Pretreating mesenchymal stem cells with interleukin-1β and transforming growth factor-β synergistically increases vascular endothelial growth factor production and improves mesenchymal stem cell-mediated myocardial protection after acute ischemia.
abstract: BACKGROUND
  Mesenchymal stem cells (MSCs) improve postischemic myocardial function in part through their secretion of growth factors such as vascular endothelial growth factor (VEGF). Pretreating MSCs with various cytokines or small molecules can improve VEGF secretion and MSC-mediated cardioprotection. However, whether 1 cytokine can potentiate the effect of another cytokine in MSC pretreatment to achieve a synergistic effect on VEGF production and cardioprotection is poorly studied.
  
  
  METHODS
  MSCs were treated with interleukin (IL)-1β and/or transforming growth factor (TGF)-β1 for 24 hours before experiments. VEGF production was determined by enzyme-linked immunosorbent assay. Isolated hearts from adult male Sprague-Dawley rats were subjected to 15 minutes of equilibration, 25 minutes of ischemia, and 40 minutes reperfusion. Hearts (n = 5-7 per group) were randomly infused with vehicle, untreated MSCs, or MSCs pretreated with IL-1β and/or TGF-β1. Specific inhibitors were used to delineate the roles of p38 mitogen-activated protein kinase (MAPK) and SMAD3 in IL-1β- and TGF-β1-mediated stimulation of MSCs.
  
  
  RESULTS
  MSCs cotreated with IL-1β and TGF-β1 exhibited synergistically increased VEGF secretion, and they greatly improved postischemic myocardial functional recovery. Ablation of p38 MAPK and SMAD3 activation with specific inhibitors negated both IL-1β- and TGF-β1-mediated VEGF production in MSCs and the ability of these pretreated MSCs to improve myocardial recovery after ischemia.
  
  
  CONCLUSIONS
  Pretreating MSCs with 2 cytokines may be useful to fully realize the potential of cell-based therapies for ischemic tissues.
authors.affiliation: Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Luo
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Poynter
authors.forename: Mariuxi C
authors.initials: MC
authors.lastname: Manukyan
authors.forename: Jeremy L
authors.initials: JL
authors.lastname: Herrmann
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Abarbanell
authors.forename: Brent R
authors.initials: BR
authors.lastname: Weil
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Meldrum
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000008:administration & dosage; D004357:Drug Synergism; D053583:Interleukin-1beta / Q000008:administration & dosage*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000502:physiology*; D051379:Mice; D008955:Models, Cardiovascular; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology / Q000628:therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D051900:Smad3 Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000008:administration & dosage*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D002316:Cardiotonic Agents; D053583:Interleukin-1beta; D051900:Smad3 Protein; C497787:Smad3 protein, rat; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D048051:p38 Mitogen-Activated Protein Kinases