title: Preconditioning of bone marrow mesenchymal stem cells by prolyl hydroxylase inhibition enhances cell survival and angiogenesis in vitro and after transplantation into the ischemic heart of rats.
abstract: BACKGROUND
  Poor cell survival and limited functional benefits have restricted the efficacy of bone marrow mesenchymal stem cells (BMSCs) in the treatment of myocardial infarction. We showed recently that hypoxia preconditioning of BMSCs and neural progenitor cells before transplantation can enhance the survival and therapeutic properties of these cells in the ischemic brain and heart. The present investigation explores a novel strategy of preconditioning BMSCs using the Hypoxia-inducible factor 1α (HIF-α) prolyl hydroxylase inhibitor dimethyloxalylglycine (DMOG) to enhance their survival and therapeutic efficacy after transplantation into infarcted myocardium.
  
  
  METHODS
  BMSCs from green fluorescent protein transgenic rats were cultured with or without 1 mM DMOG for 24 hours in complete culture medium before transplantation. Survival and angiogenic factors were evaluated in vitro by trypan blue staining, Western blotting, and tube formation test. In an ischemic heart model of rats, BMSCs with and without DMOG preconditioning were intramyocardially transplanted into the peri-infarct region 30 minutes after permanent myocardial ischemia. Cell death was measured 24 hours after engraftment. Heart function, angiogenesis and infarct size were measured 4 weeks later.
  
  
  RESULTS
  In DMOG preconditioned BMSCs (DMOG-BMSCs), the expression of survival and angiogenic factors including HIF-1α, vascular endothelial growth factor, glucose transporter 1 and phospho-Akt were significantly increased. In comparison with control cells, DMOG-BMSCs showed higher viability and enhanced angiogenesis in both in vitro and in vivo assays. Transplantation of DMOG-BMSCs reduced heart infarct size and promoted functional benefits of the cell therapy.
  
  
  CONCLUSIONS
  We suggest that DMOG preconditioning enhances the survival capability of BMSCs and paracrine effects with increased differentiation potential. Prolyl hydroxylase inhibition is an effective and feasible strategy to enhance therapeutic efficacy and efficiency of BMSC transplantation therapy after heart ischemia.
authors.forename: Xian-Bao
authors.initials: XB
authors.lastname: Liu
authors.forename: Jian-An
authors.initials: JA
authors.lastname: Wang
authors.forename: Xiao-Ya
authors.initials: XY
authors.lastname: Ji
authors.forename: Shan Ping
authors.initials: SP
authors.lastname: Yu
authors.forename: Ling
authors.initials: L
authors.lastname: Wei
mesh_terms: D000600:Amino Acids, Dicarboxylic / Q000494:pharmacology*; D000818:Animals; D016026:Bone Marrow Transplantation / Q000379:methods*; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004452:Echocardiography / Q000379:methods; D066298:In Vitro Techniques; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects*; D009203:Myocardial Infarction / Q000473:pathology / Q000628:therapy*; D018919:Neovascularization, Physiologic; D064800:Prolyl-Hydroxylase Inhibitors / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D055647:Rats, Transgenic; D019172:Transplantation Conditioning / Q000379:methods*
chemical_list: D000600:Amino Acids, Dicarboxylic; D064800:Prolyl-Hydroxylase Inhibitors; C040947:oxalylglycine