Insulin-like growth factors promote vasculogenesis in embryonic stem cells

PLoS One. 2012;7(2):e32191. doi: 10.1371/journal.pone.0032191. Epub 2012 Feb 21.

Abstract

The ability of embryonic stem cells to differentiate into endothelium and form functional blood vessels has been well established and can potentially be harnessed for therapeutic angiogenesis. However, after almost two decades of investigation in this field, limited knowledge exists for directing endothelial differentiation. A better understanding of the cellular mechanisms regulating vasculogenesis is required for the development of embryonic stem cell-based models and therapies. In this study, we elucidated the mechanistic role of insulin-like growth factors (IGF1 and 2) and IGF receptors (IGFR1 and 2) in endothelial differentiation using an embryonic stem cell embryoid body model. Both IGF1 or IGF2 predisposed embryonic stem to differentiate towards a mesodermal lineage, the endothelial precursor germ layer, as well as increased the generation of significantly more endothelial cells at later stages. Inhibition of IGFR1 signaling using neutralizing antibody or a pharmacological inhibitor, picropodophyllin, significantly reduced IGF-induced mesoderm and endothelial precursor cell formation. We confirmed that IGF-IGFR1 signaling stabilizes HIF1α and leads to up-regulation of VEGF during vasculogenesis in embryoid bodies. Understanding the mechanisms that are critical for vasculogenesis in various models will bring us one step closer to enabling cell based therapies for neovascularization.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Carrier Proteins / metabolism
  • Cell Differentiation / drug effects
  • Embryoid Bodies / cytology
  • Embryoid Bodies / drug effects
  • Embryoid Bodies / metabolism
  • Embryonic Stem Cells / cytology
  • Embryonic Stem Cells / drug effects*
  • Embryonic Stem Cells / enzymology
  • Embryonic Stem Cells / physiology*
  • Endothelium / cytology
  • Endothelium / drug effects
  • Endothelium / embryology
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Insulin-Like Growth Factor I / pharmacology*
  • Insulin-Like Growth Factor II / pharmacology*
  • Mesoderm / cytology
  • Mesoderm / drug effects
  • Mesoderm / embryology
  • Mice
  • Models, Biological
  • Neovascularization, Physiologic / drug effects*
  • Podophyllotoxin / analogs & derivatives
  • Podophyllotoxin / pharmacology
  • Protein Stability / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptor, IGF Type 1 / antagonists & inhibitors
  • Receptor, IGF Type 1 / metabolism
  • Receptor, IGF Type 2 / antagonists & inhibitors
  • Receptor, IGF Type 2 / metabolism
  • Signal Transduction / drug effects
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • Carrier Proteins
  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Receptor, IGF Type 2
  • Vascular Endothelial Growth Factor A
  • picropodophyllin
  • Insulin-Like Growth Factor I
  • Insulin-Like Growth Factor II
  • Receptor, IGF Type 1
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases
  • Podophyllotoxin