Branching of lung epithelium in vitro occurs in the absence of endothelial cells

Dev Dyn. 2015 Apr;244(4):553-63. doi: 10.1002/dvdy.24251. Epub 2015 Jan 28.


Background: Early lung morphogenesis is driven by tissue interactions. Signals from the lung mesenchyme drive epithelial morphogenesis, but which individual mesenchymal cell types are influencing early epithelial branching and differentiation remains unclear. It has been shown that endothelial cells are involved in epithelial repair and regeneration in the adult lung, and they may also play a role in driving early lung epithelial branching. These data, in combination with evidence that endothelial cells influence early morphogenetic events in the liver and pancreas, led us to hypothesize that endothelial cells are necessary for early lung epithelial branching.

Results: We blocked vascular endothelial growth factor (VEGF) signaling in embryonic day (E) 12.5 lung explants with three different VEGF receptor inhibitors (SU5416, Ki8751, and KRN633) and found that in all cases the epithelium was able to branch despite the loss of endothelial cells. Furthermore, we found that distal lung mesenchyme depleted of endothelial cells retained its ability to induce terminal branching when recombined with isolated distal lung epithelium (LgE). Additionally, isolated E12.5 primary mouse lung endothelial cells, or human lung microvascular endothelial cells (HMVEC-L), were not able to induce branching when recombined with LgE.

Conclusions: Our observations support the conclusion that endothelial cells are not required for early lung branching.

Keywords: lung development; lung differentiation; tissue interactions.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Differentiation
  • Endothelial Cells / cytology*
  • Epithelial Cells / cytology*
  • Epithelium / embryology*
  • Humans
  • Lung / embryology*
  • Lung / metabolism*
  • Lung / pathology
  • Mesoderm / metabolism
  • Mice
  • Morphogenesis
  • Mutation
  • Myocytes, Smooth Muscle / cytology
  • Pericytes / cytology
  • Receptors, Vascular Endothelial Growth Factor / metabolism
  • Signal Transduction
  • Vascular Endothelial Growth Factor A / metabolism


  • Vascular Endothelial Growth Factor A
  • Receptors, Vascular Endothelial Growth Factor