Vascular incorporation of endothelial colony-forming cells is essential for functional recovery of murine ischemic tissue following cell therapy

Theresa M Schwarz, Simon F Leicht, Tamara Radic, Iker Rodriguez-Arabaolaza, Patrick C Hermann, Frank Berger, Jaimy Saif, Wolfgang Böcker, Joachim W Ellwart, Alexandra Aicher, Christopher Heeschen

Research output: Contribution to journalArticlepeer-review

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).

METHODS AND 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.

Original languageEnglish
Pages (from-to)e13-21
JournalArteriosclerosis, Thrombosis, and Vascular biology
Volume32
Issue number2
DOIs
Publication statusPublished - Feb 2012

Keywords

  • Animals
  • Cell Proliferation
  • Cell- and Tissue-Based Therapy/methods
  • Endothelium, Vascular/cytology
  • Female
  • Ganciclovir/pharmacology
  • Hindlimb/blood supply
  • Humans
  • Ischemia/therapy
  • Mesenchymal Stem Cells/cytology
  • Mice
  • Mice, Nude
  • Models, Animal
  • Neovascularization, Physiologic/physiology
  • Phenotype
  • Recovery of Function/physiology
  • Stem Cells/cytology

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