Local and circulating endothelial cells undergo endothelial to Mesenchymal Transition (EndMT) in response to musculoskeletal injury

Shailesh Agarwal, Shawn Loder, David Cholok, Joshua Peterson, John Li, David Fireman, Christopher Breuler, Hsiao Sung Hsieh, Kavitha Ranganathan, Charles Hwang, James Drake, Shuli Li, Charles K. Chan, Michael T. Longaker, Benjamin Levi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

22 Scopus citations


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 (Δ VeCadherin/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.

Original languageEnglish
Article number32514
JournalScientific Reports
StatePublished - 12 Sep 2016
Externally publishedYes


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