Abstract
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.
Highlights
Endothelial-to-mesenchymal transition (EndMT) is a proposed process by which endothelial cells differentiate into mesenchymal cells[1]
We use a trauma-induced model of heterotopic ossification to demonstrate that even in the absence of genetic bone morphogenetic protein (BMP) receptor hyperactivity, endothelial cells are capable of undergoing EndMT
These findings suggest that EndMT occurs during the progression of trauma-induced model of heterotopic ossification (tHO)
Summary
Endothelial-to-mesenchymal transition (EndMT) is a proposed process by which endothelial cells differentiate into mesenchymal cells[1]. Despite the multitude of disorders in which EndMT has been implicated as a factor, unambiguous evidence of EndMT via lineage-tracing has remained elusive in vivo in the setting of tissue injury This is due to the use of Cre drivers which lack specificity for endothelial cells[1,3,7], non-inducible Cre systems which leave open the possibility of injury-induced promoter activity n1,7, and active immunostaining methods to identify endothelial cells which are unable to differentiate induced expression from lineage[1,3,5,7]. Those endothelial cells which trafficked to the wound site after intravenous injection underwent EndMT These findings demonstrate that a priori endothelial cells are capable of undergoing EndMT, and that this process is not restricted to local endothelial cells. These findings have clinical import, as EndMT may be inhibited by targeting TGF-βsignaling, and by targeting endothelial cell recruitment
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