title: Vascular incorporation of endothelial colony-forming cells is essential for functional recovery of murine ischemic tissue following cell therapy.
abstract: OBJECTIVE
  Cord blood-derived human endothelial colony-forming cells (ECFCs) bear a high proliferative capacity and potently enhance tissue neovascularization in vivo. Here, we investigated whether the leading mechanism for the functional improvement relates to their physical vascular incorporation or perivascular paracrine effects and whether the effects can be further enhanced by dual-cell-based therapy, including mesenchymal stem cells (MSCs).
  
  
  RESULTS
  ECFCs or MSCs were lentivirally transduced with thymidine kinase suicide gene driven by the endothelial-specific vascular endothelial growth factor 2 (kinase insert domain receptor) promoter and evaluated in a hindlimb ischemia model. ECFCs and MSCs enhanced neovascularization after ischemic events to a similar extent. Dual therapy using ECFCs and MSCs further enhanced neovascularization. Mechanistically, 3 weeks after induction of ischemia followed by cell therapy, ganciclovir-mediated elimination of kinase insert domain receptor(+) cells completely reversed the therapeutic effect of ECFCs but not that of MSCs. Histological analysis revealed that ganciclovir effectively eliminated ECFCs incorporated into the vasculature.
  
  
  CONCLUSIONS
  Endothelial-specific suicide gene technology demonstrates distinct mechanisms for ECFCs and MSCs, with complete abolishment of ECFC-mediated effects, whereas MSC-mediated effects remained unaffected. These data strengthen the notion that a dual-cell-based therapy represents a promising approach for vascular regeneration of ischemic tissue.
authors.affiliation: Stem Cell & Cancer Group, Centro Nacional de Investigaciones Oncológicas, c/ Melchor Fernández Almagro 3, 28029 Madrid, Spain.
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Schwarz
authors.forename: Simon F
authors.initials: SF
authors.lastname: Leicht
authors.forename: Tamara
authors.initials: T
authors.lastname: Radic
authors.forename: Iker
authors.initials: I
authors.lastname: Rodriguez-Arabaolaza
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Hermann
authors.forename: Frank
authors.initials: F
authors.lastname: Berger
authors.forename: Jaimy
authors.initials: J
authors.lastname: Saif
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Böcker
authors.forename: Joachim W
authors.initials: JW
authors.lastname: Ellwart
authors.forename: Alexandra
authors.initials: A
authors.lastname: Aicher
authors.forename: Christopher
authors.initials: C
authors.lastname: Heeschen
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D005260:Female; D015774:Ganciclovir / Q000494:pharmacology; D006614:Hindlimb / Q000098:blood supply*; D006801:Humans; D007511:Ischemia / Q000628:therapy*; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008819:Mice, Nude; D023421:Models, Animal; D018919:Neovascularization, Physiologic / Q000502:physiology*; D010641:Phenotype; D020127:Recovery of Function / Q000502:physiology; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology
chemical_list: D015774:Ganciclovir