Directing epithelial to mesenchymal transition through engineered microenvironments displaying orthogonal adhesive and mechanical cues
Directing epithelial to mesenchymal transition through engineered microenvironments displaying orthogonal adhesive and mechanical cues
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DOI：
10.1002/jbm.a.34068
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发表时间：
2012-08-01
影响因子：
4.9
通讯作者：
Barker, Thomas H.
中科院分区：
文献类型：
--
作者：
Markowski, Marilyn C.;Brown, Ashley C.;Barker, Thomas H.
细胞与其细胞外基质（ECM）微环境的相互作用在指导细胞过程中发挥着重要作用，这些细胞过程可以驱动伤口愈合和组织再生，但如果不受控制，则会导致病理进展。其中一个这样的过程，上皮间质转化（EMT），如果精细控制，可能在再生医学方法中具有显着的潜力。尽管最近的研究结果突出了ECM的生物化学和机械特性对EMT的影响，但仍不清楚这两种正交信号如何协同作用以控制上皮细胞表型。在这里，我们培养肺上皮细胞的纤连蛋白的细胞结合域的不同突变体的组合，优先从事特定的整合素和不同刚度的基板。我们的研究结果表明，虽然硬基板诱导自发EMT，这种反应可以克服与支持α 3和α 5整联蛋白接合的纤连蛋白片段。此外，我们发现，底物诱导的EMT与转化生长因子β激活常驻上皮细胞，是依赖于Rho/ROCK信号。抑制细胞收缩性足以维持上皮表型。我们的研究结果表明，整合素特异性参与纤连蛋白粘附结构域和ECM的力学协同作用，直接EMT。(C)2012年威利期刊公司J Biomed Mater Res Part A，2012。
Cell interactions with their extracellular matrix (ECM) microenvironments play a major role in directing cellular processes that can drive wound healing and tissue regeneration but, if uncontrolled, lead to pathological progression. One such process, epithelial to mesenchymal transition (EMT), if finely controlled could have significant potential in regenerative medicine approaches. Despite recent findings that highlight the influence of biochemical and mechanical properties of the ECM on EMT, it is still unclear how these two orthogonal cues act synergistically to control epithelial cell phenotype. Here, we cultured lung epithelial cells on combinations of different mutants of fibronectin's cell binding domain that preferentially engage specific integrins and substrates of varying stiffness. Our results suggest that while stiff substrates induce spontaneous EMT, this response can be overcome by with fragments of fibronectin that support a3 and a5 integrin engagement. Furthermore, we found that substrate-induced EMT correlates with transforming growth factor beta activation by resident epithelial cells and is dependent on Rho/ROCK signaling. Suppressing cell-contractility was sufficient to maintain an epithelial phenotype. Our results suggest that integrin-specific engagement of fibronectin adhesive domains and the mechanics of the ECM act synergistically to direct EMT.(C) 2012 Wiley Periodicals, Inc. J Biomed Mater Res Part A, 2012.