Local and Circulating Endothelial Cells Undergo Endothelial to Mesenchymal Transition (EndMT) in Response to Musculoskeletal Injury

Sci Rep. 2016 Sep 12;6:32514. doi: 10.1038/srep32514.


Endothelial-to-mesenchymal transition (EndMT) has been implicated in a variety of aberrant wound healing conditions. However, unambiguous evidence of EndMT has been elusive due to limitations of in vitro experimental designs and animal models. In vitro experiments cannot account for the myriad ligands and cells which regulate differentiation, and in vivo tissue injury models may induce lineage-independent endothelial marker expression in mesenchymal cells. By using an inducible Cre model to mark mesenchymal cells (Scx-creERT/tdTomato + ) prior to injury, we demonstrate that musculoskeletal injury induces expression of CD31, VeCadherin, or Tie2 in mesenchymal cells. VeCadherin and Tie2 were expressed in non-endothelial cells (CD31-) present in marrow from uninjured adult mice, thereby limiting the specificity of these markers in inducible models (e.g. VeCadherin- or Tie2-creERT). However, cell transplantation assays confirmed that endothelial cells (ΔVeCadherin/CD31+/CD45-) isolated from uninjured hindlimb muscle tissue undergo in vivo EndMT when transplanted directly into the wound without intervening cell culture using PDGFRα, Osterix (OSX), SOX9, and Aggrecan (ACAN) as mesenchymal markers. These in vivo findings support EndMT in the presence of myriad ligands and cell types, using cell transplantation assays which can be applied for other pathologies implicated in EndMT including tissue fibrosis and atherosclerosis. Additionally, endothelial cell recruitment and trafficking are potential therapeutic targets to prevent EndMT.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aggrecans / genetics
  • Aggrecans / metabolism
  • Animals
  • Burns, Electric / genetics*
  • Burns, Electric / metabolism
  • Burns, Electric / pathology
  • Cadherins / genetics
  • Cadherins / metabolism
  • Cell Differentiation
  • Endothelial Cells / metabolism*
  • Endothelial Cells / pathology
  • Endothelial Cells / transplantation
  • Epithelial-Mesenchymal Transition / genetics*
  • Gene Expression
  • Hindlimb
  • Leukocyte Common Antigens / genetics
  • Leukocyte Common Antigens / metabolism
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Male
  • Mesenchymal Stem Cells / metabolism*
  • Mesenchymal Stem Cells / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Platelet Endothelial Cell Adhesion Molecule-1 / genetics
  • Platelet Endothelial Cell Adhesion Molecule-1 / metabolism
  • Primary Cell Culture
  • Receptor, Platelet-Derived Growth Factor alpha / genetics
  • Receptor, Platelet-Derived Growth Factor alpha / metabolism
  • Receptor, TIE-2 / genetics
  • Receptor, TIE-2 / metabolism
  • SOX9 Transcription Factor / genetics
  • SOX9 Transcription Factor / metabolism
  • Sp7 Transcription Factor / genetics
  • Sp7 Transcription Factor / metabolism
  • Tenotomy


  • Aggrecans
  • Cadherins
  • Luminescent Proteins
  • Platelet Endothelial Cell Adhesion Molecule-1
  • SOX9 Transcription Factor
  • Sox9 protein, mouse
  • Sp7 Transcription Factor
  • Sp7 protein, mouse
  • red fluorescent protein
  • Receptor, Platelet-Derived Growth Factor alpha
  • Receptor, TIE-2
  • Tek protein, mouse
  • Leukocyte Common Antigens
  • Ptprc protein, mouse