Oxygen sensing mesenchymal progenitors promote neo-vasculogenesis in a humanized mouse model in vivo

PLoS One. 2012;7(9):e44468. doi: 10.1371/journal.pone.0044468. Epub 2012 Sep 7.

Abstract

Despite insights into the molecular pathways regulating hypoxia-induced gene expression, it is not known which cell types accomplish oxygen sensing during neo-vasculogenesis. We have developed a humanized mouse model of endothelial and mesenchymal progenitor co-transplantation to delineate the cellular compartments responsible for hypoxia response during vasculogenesis. Mesenchymal stem/progenitor cells (MSPCs) accumulated nuclear hypoxia-inducible transcription factor (HIF)-1α earlier and more sensitively than endothelial colony forming progenitor cells (ECFCs) in vitro and in vivo. Hypoxic ECFCs showed reduced function in vitro and underwent apoptosis within 24h in vivo when used without MSPCs. Surprisingly, only in MSPCs did pharmacologic or genetic inhibition of HIF-1α abrogate neo-vasculogenesis. HIF deletion in ECFCs caused no effect. ECFCs could be rescued from hypoxia-induced apoptosis by HIF-competent MSPCs resulting in the formation of patent perfused human vessels. Several angiogenic factors need to act in concert to partially substitute mesenchymal HIF-deficiency. Results demonstrate that ECFCs require HIF-competent vessel wall progenitors to initiate vasculogenesis in vivo and to bypass hypoxia-induced apoptosis. We describe a novel mechanistic role of MSPCs as oxygen sensors promoting vasculogenesis thus underscoring their importance for the development of advanced cellular therapies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Blotting, Western
  • Fluorescent Antibody Technique
  • Humans
  • Immunohistochemistry
  • Mesenchymal Stem Cells / cytology
  • Mesenchymal Stem Cells / metabolism*
  • Mice
  • Models, Animal*
  • Neovascularization, Physiologic*
  • Oxygen / metabolism*
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • Vascular Endothelial Growth Factor A
  • Oxygen

Grant support

This work was supported by the Austrian Research Foundation (FFG, grant N211-NAN; DS), the Adult Stem Cell Research Foundation (TASCRF) and a young investigator starting grant of the Medical University of Graz (AR). NAH, AO, AR and RR are fellows of the PhD program Molecular Medicine at the Medical University of Graz. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.