Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA.
Cells Tissues Organs. 2013;197(6):435-44. doi: 10.1159/000348415. Epub 2013 Jun 14.
During the epithelial to mesenchymal transition (EMT), polarized cells in the epithelium can undergo a transformation characterized by the loss of cell-cell junctions and increased migratory activity into nonpolarized invasive cells. These cells adopt a mesenchymal shape and migrate into the basal lamina. Such transitions have been observed in developmental processes and have been linked to cancer cell metastasis. Most experimental studies on EMT search for molecular markers indicating an epithelial or mesenchymal conformation, focussing on afferent signaling pathways received by cells undergoing this transformation; however, these approaches are unable to track mechanical changes in the cell and the possible role this plays in EMT. In order to address this gap in our understanding, we have used a quantitative approach to study population level effects of single cell changes typically occurring during EMT. We have developed a computational model making use of the advantages of both single cell migratory models and agent-based cell population models to study the effect of cellular molecular processes in EMT. The disruption of a cell sheet representing the epithelium over a dense extracellular matrix (ECM) is simulated using interaction forces between different cells and between cells and discrete fibers representing the ECM. In our study, two different parameters were varied: protrusion force magnitude and E-cadherin (cell-cell junction) concentration. The cell population was tracked for 3 days and the number of cells that leave the layer, the depth of invasion, and the percentage of initial number of cells that remain in the layer (a measure of epithelium disruption) were monitored. Our studies suggest that having a high protrusion force or a reduction in cell-cell attachments is enough to cause EMT. Our results also demonstrate that the morphological progression in membrane disruption has an effect on the number of cells becoming invasive, with epithelial layers broken into clusters hindering the further exodus of cells. The results reveal the quantitative interplay between two key parameters involved in EMT and suggest potential avenues for further exploration of a systems level understanding of EMT.
在上皮细胞-间充质转化（EMT）过程中，上皮细胞中的极化细胞可以经历一种转化，其特征是细胞-细胞连接的丧失和迁移活性的增加，变成非极化的侵袭细胞。这些细胞采用间充质形状并迁移到基底膜中。这种转化在发育过程中已经观察到，并与癌细胞转移有关。EMT 的大多数实验研究都在寻找指示上皮或间充质构象的分子标记物，重点关注经历这种转化的细胞接收的传入信号通路；然而，这些方法无法跟踪细胞中的机械变化及其在 EMT 中可能发挥的作用。为了解决我们理解中的这一差距，我们使用定量方法研究 EMT 过程中通常发生的单细胞变化对群体水平的影响。我们开发了一种计算模型，利用单细胞迁移模型和基于代理的细胞群体模型的优势来研究 EMT 中细胞分子过程的影响。使用不同细胞之间以及代表细胞外基质（ECM）的离散纤维之间的相互作用力模拟代表上皮的细胞片的破坏。在我们的研究中，两个不同的参数发生了变化：突起力的大小和 E-钙粘蛋白（细胞-细胞连接）的浓度。跟踪细胞群体 3 天，监测离开层的细胞数量、入侵深度以及留在层中的初始细胞数量的百分比（上皮破坏的度量）。我们的研究表明，具有高突起力或减少细胞-细胞附着足以引起 EMT。我们的结果还表明，膜破坏的形态进展对侵袭细胞的数量有影响，上皮层破裂成簇，阻碍了细胞的进一步流出。结果揭示了 EMT 中两个关键参数之间的定量相互作用，并为进一步探索 EMT 的系统水平理解提供了潜在途径。
