Schroer Alison K, Ryzhova Larisa M, Merryman W David
Department of Biomedical Engineering, Vanderbilt University, Room 9445D, MRB4 2213 Garland Ave, Nashville, TN 37232, USA.
Cell Mol Bioeng. 2014 Sep;7(3):446-459. doi: 10.1007/s12195-014-0344-9. Epub 2014 Jul 6.
Fibrotic disease is a major cause of morbidity and mortality and is characterized by the transition of resident fibroblast cells into active myofibroblasts, identified by their expression of alpha smooth muscle actin. Myofibroblast differentiation is regulated by growth factor signaling and mechanical signals transduced through integrins, which converge at focal adhesion proteins (Src and FAK) and MAPK signaling, but lead to divergent outcomes. While details are known about individual pathways, little is known about their interactions. To this end, an ODE-based model of this cell signaling network was developed in parallel with experiments to analyze potential mechanisms of crosstalk and regulation of SMA production. We found that cells lacking Src or FAK produce significantly less or more SMA than wild type cells, respectively. Transforming growth factor beta 1 and fibroblast growth factor signal through ERK and MAPK p38 with different dynamic profiles to increase or decrease SMA expression, respectively. Our model effectively recreated SMA expression levels across a set of 22 experimental conditions and matched some features of transient phosphorylation of ERK and p38. These results support a potential mechanism for regulation of fibroblast differentiation: SMA production is promoted by active p38 and Src and opposed by ERK.
纤维化疾病是发病和死亡的主要原因，其特征是驻留的成纤维细胞转变为活跃的肌成纤维细胞，可通过α平滑肌肌动蛋白的表达来识别。肌成纤维细胞的分化受生长因子信号传导和通过整合素转导的机械信号调节，这些信号在粘着斑蛋白（Src和FAK）和MAPK信号传导处汇聚，但会导致不同的结果。虽然对各个途径的细节有所了解，但对它们之间的相互作用却知之甚少。为此，在进行实验的同时，开发了一个基于常微分方程的该细胞信号网络模型，以分析串扰和SMA产生调控的潜在机制。我们发现，缺乏Src或FAK的细胞分别比野生型细胞产生明显更少或更多的SMA。转化生长因子β1和成纤维细胞生长因子分别通过具有不同动态特征的ERK和MAPK p38发出信号，以增加或降低SMA表达。我们的模型有效地再现了22种实验条件下的SMA表达水平，并与ERK和p38瞬时磷酸化的一些特征相匹配。这些结果支持了一种成纤维细胞分化调控的潜在机制：活跃的p38和Src促进SMA的产生，而ERK则起相反作用。
