Local and Circulating Endothelial Cells Undergo Endothelial to Mesenchymal Transition (EndMT) in Response to Musculoskeletal Injury.
Local and Circulating Endothelial Cells Undergo Endothelial to Mesenchymal Transition (EndMT) in Response to Musculoskeletal Injury.
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DOI：
10.1038/srep32514
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发表时间：
2016-09-12
影响因子：
4.6
通讯作者：
Levi B
中科院分区：
文献类型：
--
作者：
Agarwal S;Loder S;Cholok D;Peterson J;Li J;Fireman D;Breuler C;Hsieh HS;Ranganathan K;Hwang C;Drake J;Li S;Chan CK;Longaker MT;Levi B
内皮-间充质转化（EndMT）与多种异常伤口愈合条件有关。然而，由于体外实验设计和动物模型的限制，EndMT的明确证据一直难以捉摸。体外实验不能解释调节分化的无数配体和细胞，并且体内组织损伤模型可以诱导间充质细胞中的谱系非依赖性内皮标志物表达。通过使用诱导型Cre模型在损伤前标记间充质细胞（Scx-creERT/tdTomato +），我们证明了肌肉骨骼损伤诱导间充质细胞中CD 31、VeCadherin或Tie 2的表达。VeCadherin和Tie 2在未受伤成年小鼠骨髓中存在的非内皮细胞（CD 31 −）中表达，从而限制了这些标记物在诱导型模型（例如VeCadherin-或Tie 2-creERT）中的特异性。然而，细胞移植试验证实，从未受伤的后肢肌肉组织中分离的内皮细胞（ΔVeCadherin/CD 31 +/CD 45 −）在直接移植到伤口中时经历了体内EndMT，而无需使用PDGFRα、Osterix（OSX）、SOX 9和聚集蛋白聚糖（ACAN）作为间充质标记物进行干预细胞培养。这些体内发现支持EndMT在无数配体和细胞类型的存在下，使用细胞移植测定，其可应用于EndMT中涉及的其他病理，包括组织纤维化和动脉粥样硬化。此外，内皮细胞募集和运输是预防EndMT的潜在治疗靶点。
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.
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影响因子：
8.8
作者：
Chen PY;Qin L;Barnes C;Charisse K;Yi T;Zhang X;Ali R;Medina PP;Yu J;Slack FJ;Anderson DG;Kotelianski V;Wang F;Tellides G;Simons M
通讯作者：
Simons M
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82.9
作者：
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通讯作者：
Kalluri, Raghu
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82.9
作者：
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通讯作者：
Gurtner, GC
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37.8
作者：
Kovacic JC;Mercader N;Torres M;Boehm M;Fuster V
通讯作者：
Fuster V
影响因子：
4.1
作者：
Kolind, Mille;Bobyn, Justin D.;Schindeler, Aaron
通讯作者：
Schindeler, Aaron