title: Therapeutic angiogenesis of human early endothelial progenitor cells is enhanced by thrombomodulin.
abstract: OBJECTIVE
  We examined the effect of thrombomodulin (TM) domains 2 and 3 (TMD23) on human early endothelial progenitor cells (EPCs).
  
  
  RESULTS
  TM was expressed and released by human EPCs cultured from peripheral blood mononuclear cells (PBMCs). Addition of TMD23 (100 ng/mL) to the cultured PBMCs increased the colony-forming units, chemotactic motility, matrix metalloproteinase activity, and interleukin-8 secretion but decreased tumor necrosis factor-α (TNF-α) release. Analysis of the signal pathway showed that TMD23 activated Akt. Inhibition of phosphatidylinositol-3 kinase-Akt blocked the effects of TMD23 on chemotactic motility, matrix metalloproteinase-9, interleukin-8, and TNF-α. In hindlimb ischemia mice, laser Doppler perfusion imaging of the ischemic limb during the 21 days after arterial ligation showed that the perfusion recovered best with intraperitoneal infusion of TMD23 plus local injection of early EPCs, followed by either infusion of TMD23 or injection of the cells. Animals without either treatment had the worst results. Animals treated with TMD23 also had lower circulating and tissue levels of TNF-α.
  
  
  CONCLUSIONS
  TM is expressed and released by human circulating EPCs. Exogenous TMD23 enhances the angiogenic potential of early EPCs in vitro through activation of phosphatidylinositol-3 kinase-Akt pathway. Coadministration of TMD23 plus early EPCs augments therapeutic angiogenesis of the EPCs in ischemic tissues.
authors.affiliation: Department of Surgery, Mackay Memorial Hospital, Mackay Medical College, New Taipei City, Taiwan.
authors.forename: Jiun-Yi
authors.initials: JY
authors.lastname: Li
authors.forename: Cheng-Huang
authors.initials: CH
authors.lastname: Su
authors.forename: Yih-Jer
authors.initials: YJ
authors.lastname: Wu
authors.forename: Ting-Yi
authors.initials: TY
authors.lastname: Tien
authors.forename: Chin-Ling
authors.initials: CL
authors.lastname: Hsieh
authors.forename: Chih-Hao
authors.initials: CH
authors.lastname: Chen
authors.forename: Ya-Ming
authors.initials: YM
authors.lastname: Tseng
authors.forename: Guey-Yueh
authors.initials: GY
authors.lastname: Shi
authors.forename: Hua-Lin
authors.initials: HL
authors.lastname: Wu
authors.forename: Cheng-Ho
authors.initials: CH
authors.lastname: Tsai
authors.forename: Fang-Yue
authors.initials: FY
authors.lastname: Lin
authors.forename: Hung-I
authors.initials: HI
authors.lastname: Yeh
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology*; D005260:Female; D006614:Hindlimb / Q000098:blood supply; D006801:Humans; D007511:Ischemia / Q000503:physiopathology / Q000628:therapy; D007963:Leukocytes, Mononuclear / Q000166:cytology; D051379:Mice; D008819:Mice, Nude; D023421:Models, Animal; D018919:Neovascularization, Physiologic / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D018180:Thrombomodulin / Q000627:therapeutic use*
chemical_list: D018180:Thrombomodulin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt