A Mechanical Instability in Planar Epithelial Monolayers Leads to Cell Extrusion
A Mechanical Instability in Planar Epithelial Monolayers Leads to Cell Extrusion
复制标题
DOI：
10.1016/j.bpj.2020.03.028
复制
发表时间：
2020-05-19
影响因子：
3.4
通讯作者：
Fujimoto, Koichi
中科院分区：
文献类型：
--
作者：
Okuda, Satoru;Fujimoto, Koichi
在细胞挤出中，嵌入上皮单层中的细胞失去其顶面或底面，随后被相邻细胞挤出单层。细胞挤出发生在细胞凋亡、上皮-间质转化或癌前细胞侵袭期间。它们在胚胎发生、稳态、癌发生和许多其他生物过程中起重要作用。虽然许多参与细胞挤出的分子因素是已知的，但对细胞挤出的机械基础知之甚少。我们使用了一个三维（3D）顶点模型，以调查的机械稳定性的细胞排列在一个单层与3D泡沫几何形状。我们发现，当构成单层的细胞具有均匀的机械性能时，当3D几何形状的对称性被破坏时，细胞被挤出单层，因为细胞密度增加或单个细胞周围的拓扑邻居的数量减少。这些结果表明，上皮单层的3D泡沫几何形状中固有的机械不稳定性足以驱动上皮细胞挤出。在单层中的细胞在内在遗传程序的控制下主动产生收缩力或粘附力的情况下，这些力用于破坏单层的对称性，导致细胞挤出，其通过顶侧和基底侧上的收缩力和粘附力的平衡被引导至单层的顶侧或基底侧。虽然我们的分析是基于一个简单的力学模型，我们的结果是根据观察上皮细胞单层在体内和一致的解释细胞挤出在广泛的生理和病理生理条件下。我们的研究结果说明了细胞挤出的机械理解的重要性，并提供了一个基础，通过它链接到物理过程的分子调控。
In cell extrusion, a cell embedded in an epithelial monolayer loses its apical or basal surface and is subsequently squeezed out of the monolayer by neighboring cells. Cell extrusions occur during apoptosis, epithelial-mesenchymal transition, or precancerous cell invasion. They play important roles in embryogenesis, homeostasis, carcinogenesis, and many other biological processes. Although many of the molecular factors involved in cell extrusion are known, little is known about the mechanical basis of cell extrusion. We used a three-dimensional (3D) vertex model to investigate the mechanical stability of cells arranged in a monolayer with 3D foam geometry. We found that when the cells composing the monolayer have homogeneous mechanical properties, cells are extruded from the monolayer when the symmetry of the 3D geometry is broken because of an increase in cell density or a decrease in the number of topological neighbors around single cells. Those results suggest that mechanical instability inherent in the 3D foam geometry of epithelial monolayers is sufficient to drive epithelial cell extrusion. In the situation in which cells in the monolayer actively generate contractile or adhesive forces under the control of intrinsic genetic programs, the forces act to break the symmetry of the monolayer, leading to cell extrusion that is directed to the apical or basal side of the monolayer by the balance of contractile and adhesive forces on the apical and basal sides. Although our analyses are based on a simple mechanical model, our results are in accordance with observations of epithelial monolayers in vivo and consistently explain cell extrusions under a wide range of physiological and pathophysiological conditions. Our results illustrate the importance of a mechanical understanding of cell extrusion and provide a basis by which to link molecular regulation to physical processes.