Department of Biomedical Engineering, Binghamton University, Binghamton, New York, USA.
Department of Mechanical Engineering, Binghamton University, Binghamton, New York, USA.
J Biomed Mater Res A. 2017 Oct;105(10):2729-2741. doi: 10.1002/jbm.a.36133. Epub 2017 Jun 27.
Alterations in shear stress, mechanical deformation, extracellular matrix (ECM) composition and exposure to inflammatory conditions are known to cause endothelial to mesenchymal transformation (EndMT). This change in endothelial phenotype has only recently been linked to adult pathologies such as cancer progression, organ fibrosis, and calcific aortic valve disease; and its function in adult physiology, especially in response to tissue mechanics, has not been rigorously investigated. EndMT is a response to mechanical and biochemical signals that results in the remodeling of underlying tissues. In diseased aortic valves, glycosaminoglycans (GAGs) are present in the collagen-rich valve fibrosa, and are deposited near calcified nodules. In this study, in vitro models of early and late-stage valve disease were developed by incorporating the GAGs chondroitin sulfate (CS), hyaluronic acid, and dermatan sulfate into 3D collagen hydrogels with or without exposure to TGF-β1 to simulate EndMT in response to microenvironmental changes. High levels of CS induced the highest rate of EndMT and led to the most collagen I and GAG production by mesenchymally transformed cells, which indicates a cell phenotype most likely to promote fibrotic disease. Mesenchymal transformation due to altered ECM was found to depend on cell-ECM bond strength and extracellular signal-regulated protein kinases 1/2 signaling. Determining the environmental conditions that induce and promote EndMT, and the subsequent behavior of mesenchymally transformed cells, will advance understanding on the role of endothelial cells in tissue regeneration or disease progression. © 2017 Wiley Periodicals Inc. J Biomed Mater Res Part A: 105A: 2729-2741, 2017.
剪切应力、机械变形、细胞外基质（ECM）组成和炎症环境暴露的改变已知会导致内皮细胞向间充质转化（EndMT）。这种内皮表型的变化最近才与癌症进展、器官纤维化和钙化主动脉瓣疾病等成人疾病有关，其在成人生理学中的功能，特别是对组织力学的反应，尚未得到严格研究。EndMT 是对机械和生化信号的反应，导致基底组织的重塑。在患病的主动脉瓣中，糖胺聚糖（GAGs）存在于富含胶原蛋白的瓣纤维中，并沉积在钙化结节附近。在这项研究中，通过将糖胺聚糖硫酸软骨素（CS）、透明质酸和硫酸皮肤素纳入 3D 胶原蛋白水凝胶中，并在 TGF-β1 存在或不存在的情况下模拟对微环境变化的 EndMT，开发了早期和晚期瓣膜疾病的体外模型。CS 的高浓度诱导最高的 EndMT 率，并导致间充质转化细胞产生最多的胶原蛋白 I 和 GAG，这表明最有可能促进纤维化疾病的细胞表型。由于 ECM 改变而导致的间充质转化被发现取决于细胞-ECM 键强度和细胞外信号调节蛋白激酶 1/2 信号。确定诱导和促进 EndMT 的环境条件，以及间充质转化细胞的随后行为，将推进对内皮细胞在组织再生或疾病进展中的作用的理解。© 2017 年 Wiley 期刊公司。J 生物医学材料研究 A 部分：105A：2729-2741，2017 年。
