Rausch Sebastian, Das Tamal, Soiné Jérôme R D, Hofmann Tobias W, Boehm Christian H J, Schwarz Ulrich S, Boehm Heike, Spatz Joachim P
Department of New Materials and Biosystems, Max Planck Institute for Intelligent Systems, Heisenbergstr. 3, 70569, Stuttgart, Germany,
Biointerphases. 2013 Dec;8(1):32. doi: 10.1186/1559-4106-8-32. Epub 2013 Nov 22.
The collective migration of cells is fundamental to epithelial biology. One of the hallmarks of collective behavior in migrating cohesive epithelial cell sheets is the emergence of so called leader cells. These cells exhibit a distinct morphology with a large and highly active lamellipodium. Although it is generally accepted that they play a crucial part in collective migration, the biophysical factors that regulate their formation remain unknown.Here we show that a geometry-based cue like local variation of curvature of the collective's perimeter is capable of triggering leader cell formation and promoting enhanced motility at defined positions. Remarkably, the extent of this effect scales with the magnitude of the curvature.Cytoskeletal tension was found to be important for geometry induced leader cell formation, as cells treated with tension reducing agents appeared less sensitive to local curvature variation. Accordingly, traction force microscopy revealed an increased level of shear stress at highly curved positions even before the cell migration had actually started, indicating the presence of a collective polarization induced by the geometry of the confinement.Together our findings suggest that high curvature leads to locally increased stress accumulation, mediated via cell-substrate interaction as well as via cytoskeleton tension. The stress accumulation in turn enhances the probability of leader cell formation as well as cell motility. This work defines the importance of geometric cue such as local curvature in the collective migration dynamics of epithelial cells and thus shows implications for the biophysical regulation of epithelium during wound healing, embryonic development, and oncogenesis.
细胞的集体迁移是上皮生物学的基础。在迁移的紧密上皮细胞层中，集体行为的一个标志是所谓的引导细胞的出现。这些细胞呈现出独特的形态，具有大且高度活跃的片状伪足。尽管人们普遍认为它们在集体迁移中起着关键作用，但调节其形成的生物物理因素仍然未知。在这里，我们表明，基于几何形状的线索，如集体边界曲率的局部变化，能够触发引导细胞的形成，并在特定位置促进增强的运动性。值得注意的是，这种效应的程度与曲率的大小成比例。发现细胞骨架张力对于几何形状诱导的引导细胞形成很重要，因为用降低张力的试剂处理的细胞对局部曲率变化似乎不太敏感。相应地，牵引力显微镜显示，甚至在细胞迁移实际开始之前，在高度弯曲的位置剪切应力水平就有所增加，这表明存在由限制几何形状诱导的集体极化。我们的研究结果共同表明，高曲率导致局部应力积累增加，这是通过细胞 - 基质相互作用以及细胞骨架张力介导的。应力积累反过来又增加了引导细胞形成以及细胞运动性的概率。这项工作定义了几何线索（如局部曲率）在上皮细胞集体迁移动力学中的重要性，从而显示了其在伤口愈合、胚胎发育和肿瘤发生过程中上皮生物物理调节方面的意义。
