Matrix Rigidity Mediates TGFβ1-Induced Epithelial-Myofibroblast Transition by Controlling Cytoskeletal Organization and MRTF-A Localization
Matrix Rigidity Mediates TGFβ1-Induced Epithelial-Myofibroblast Transition by Controlling Cytoskeletal Organization and MRTF-A Localization
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DOI：
10.1002/jcp.24895
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发表时间：
2015-08-01
影响因子：
5.6
通讯作者：
Gomez, Esther W.
中科院分区：
文献类型：
--
作者：
O'Connor, Joseph W.;Riley, Patrick N.;Gomez, Esther W.
肌成纤维细胞介导正常的伤口愈合，并且在慢性活化时可以促进病理状况的发展，包括器官纤维化和癌症。肌成纤维细胞可以通过上皮-间充质转化（EMT）从上皮细胞发育，在EMT期间上皮细胞表现出剧烈的形态变化并上调细胞骨架相关蛋白，从而能够发挥大的收缩力并重塑周围微环境。基质刚性增加是纤维化和肿瘤进展的标志，机械张力已被确定为EMT的调节剂;然而，管理EMT的机械调节的机制尚未完全理解。在这里，我们发现，基质刚性调节转化生长因子（TGF）-1诱导的EMT，刚性基质使肌成纤维细胞标志物表达增加，细胞形态学变化，和细胞骨架重组，而软基质阻止这些变化。此外，我们发现，基质刚性控制心肌蛋白相关转录因子（MRTF）-A，细胞骨架蛋白表达的调节器，有助于在EMT过程中肌源性功能的收购亚细胞定位。这些研究的结果提供了对生物物理学线索如何促进上皮细胞的肌成纤维细胞发育的深入了解，并可能提出增强伤口愈合或设计纤维化和癌症治疗方案的方法。J.细胞。230：1829-1839，2015。(c)2014 Wiley Periodicals，Inc.
Myofibroblasts mediate normal wound healing and upon chronic activation can contribute to the development of pathological conditions including organ fibrosis and cancer. Myofibroblasts can develop from epithelial cells through an epithelial-mesenchymal transition (EMT) during which epithelial cells exhibit drastic morphological changes and upregulate cytoskeletal associated proteins that enable exertion of large contractile forces and remodeling of the surrounding microenvironment. Increased matrix rigidity is a hallmark of fibrosis and tumor progression and mechanical tension has been identified as a regulator of EMT; however, the mechanisms governing the mechanical regulation of EMT are not completely understood. Here, we find that matrix rigidity regulates transforming growth factor (TGF)-1-induced EMT, with rigid substrata enabling increased myofibroblast marker expression, cell morphology changes, and cytoskeletal reorganization while soft matrices block these changes. Furthermore, we find that matrix rigidity controls the subcellular localization of myocardin related transcription factor (MRTF)-A, a regulator of cytoskeletal protein expression that contributes to the acquisition of myogenic features during EMT. Results from these studies provide insight into how biophysical cues contribute to myofibroblast development from epithelial cells and may suggest ways to enhance wound healing or to engineer therapeutic solutions for fibrosis and cancer. J. Cell. Physiol. 230: 1829-1839, 2015. (c) 2014 Wiley Periodicals, Inc.