Chemical and Systems Biology, Bio-X Program, Stanford University, 318 Campus Drive, Stanford, CA 94305-5439, USA.
Mol Cell Biol. 2011 Jan;31(2):342-50. doi: 10.1128/MCB.00800-10. Epub 2010 Oct 25.
Cells in endothelial cell monolayers maintain a tight barrier between blood and tissue, but it is not well understood how endothelial cells move within monolayers, pass each other, migrate when stimulated with growth factor, and also retain monolayer integrity. Here, we develop a quantitative steering model based on functional classes of genes identified previously in a small interfering RNA (siRNA) screen to explain how cells locally coordinate their movement to maintain monolayer integrity and collectively migrate in response to growth factor. In the model, cells autonomously migrate within the monolayer and turn in response to mechanical cues resulting from adhesive, drag, repulsive, and directed steering interactions with neighboring cells. We show that lateral-drag steering explains the local coordination of cell movement and the maintenance of monolayer integrity by allowing closure of small lesions. We further demonstrate that directional steering of cells at monolayer boundaries, combined with adhesive steering of cells behind, can explain growth factor-triggered collective migration into open space. Together, this model provides a mechanistic explanation for the observed genetic modularity and a conceptual framework for how cells can dynamically maintain sheet integrity and undergo collective directed migration.
内皮细胞单层中的细胞在血液和组织之间维持着紧密的屏障，但人们对于内皮细胞如何在单层中移动、如何相互穿过、在受到生长因子刺激时如何迁移以及如何保持单层完整性还不太了解。在这里，我们基于之前在小干扰 RNA (siRNA) 筛选中鉴定的功能基因类别，开发了一种定量导向模型，以解释细胞如何局部协调其运动以维持单层完整性，并在受到生长因子刺激时集体迁移。在该模型中，细胞在单层内自主迁移，并根据与相邻细胞的粘附、拖拽、排斥和定向导向相互作用产生的机械线索转向。我们表明，侧向拖拽导向通过允许小损伤的闭合，解释了细胞运动的局部协调和单层完整性的维持。我们进一步证明，在单层边界处对细胞进行定向导向，结合对细胞后面的粘附导向，可以解释生长因子触发的向开阔空间的集体迁移。总的来说，该模型为观察到的遗传模块性提供了一个机械解释，并为细胞如何能够动态地维持薄片完整性并进行集体定向迁移提供了一个概念框架。
