Mechanics of Monolayer Migration

描述(申请人提供)：肺中的细胞通常不是作为单独的实体迁移，而是以集体的片状、导管、链或簇的形式迁移。但是，每个细胞如何协调自己的迁移与邻近细胞的迁移，这一点令人费解。我们在这里提出了一个假设，即细胞协调迁移的一个被忽视但仍然是核心的特征是，每个组成细胞可能会受到最近邻居的物理限制(干扰)。干扰假说看起来很简单，但却使机械性预测成为令人惊讶、复杂和可测试的先验。它预测：1)如果没有邻近细胞的协同运动，整合的单层内的细胞就不能迁移；2)这种协作性阻碍了系统的动力学，并通过在多个组织尺度上通过系统波动的显著不同的力链的自发出现来做到这一点；以及3)减少黏附相互作用，或减少压缩应力，或增加潮汐变形，如在呼吸和机械通风中发生的，所有这些都有助于促进细胞的解堵和解体，并且都由一个统一的干扰相图来描述。利用一种独特的实验平台的原型--单层应力显微镜--我们已经获得了支持这一新的物理图像的初步数据。如果这一假说被证明具有预测能力，这一假说将在一个机制标准下将上皮和内皮单层生理学以及修复、屏障功能、纤维化和上皮-间充质转化(EMT)中的集体板层迁移的不同方面结合在一起。

DESCRIPTION (provided by applicant): Cells in the lung often migrate not as individual entities but as collective sheets, ducts, strands, or clusters. But how each cell can coordinate its migration with that of immediate neighbors has defied full comprehension. We propose here the hypothesis that a much overlooked but nonetheless central feature of coordinated cellular migration is that each constituent cell can become physically constrained (jammed) by nearest neighbors. The jamming hypothesis is deceptively simple, yet makes mechanistic predictions a priori that are surprising, complex, and testable. It predicts: 1) that a cell within the integrated monolayer cannot migrate without cooperative motions of its immediate neighbors; 2) that this cooperativity retards system dynamics, and does so through spontaneous emergence of dramatically heterogeneous force chains that ripple through the system at multiple scales of organization; and 3) that decreasing adhesive interactions, or decreasing compressive stresses, or increasing tidal deformations as occur in breathing and mechanical ventilation, all serve to pro- mote cell unjamming and disaggregation, and are all described by a unified jamming phase diagram. Using a prototype of a unique experimental platform -Monolayer Stress Microscopy- we have obtained preliminary data supporting this novel physical picture. If it is shown to have predictive power, this hypothesis would bring together under one mechanistic rubric diverse aspects of collective sheet migrations in epithelial and endothelial monolayer physiology, as well as in repair, barrier function, fibrosis, and the epithelial-mesenchymal transition (EMT).