Mechanics of Monolayer Migration

描述（由申请人提供）：肺中的细胞通常不是作为单个实体迁移，而是作为集合片、导管、束或簇迁移。但是，每个细胞如何协调其与近邻细胞的迁移，还没有完全理解。我们在这里提出的假设，一个被忽视的，但协调细胞迁移的中心特征是，每个组成细胞可以成为物理约束（堵塞）最近的邻居。干扰假说看似简单，但它的先验机制预测却令人惊讶、复杂且可检验。它预测：1）在整合单层内的细胞不能在没有其紧邻的细胞的合作运动的情况下迁移; 2）这种合作性阻碍了系统动力学，并且通过自发出现在多个组织尺度上涟漪通过系统的显著异质力链来实现;和3）减少粘附相互作用，或减少压缩应力，或增加在呼吸和机械通气中发生的潮汐变形，都用于促进小区解除干扰和分解，并且都由统一的干扰相位图描述。使用一个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。如果它被证明具有预测能力，这种假设将汇集在一个机制的标题下，在上皮和内皮细胞单层生理学，以及在修复，屏障功能，纤维化，和上皮-间充质转化（EMT）的集体片迁移的各个方面。 公共卫生相关性：我们团队的最新技术和概念进展1 -13表明，肺和其他器官系统中细胞单层的力学可能受一种称为干扰过渡的状态变化所支配。这种新的视角在逻辑上导致了重要的新问题。例如，在正常的生理学中，细胞单层是否会因为组成细胞的堵塞而倾向于形成固体状的聚集层--具有良好的屏障功能，细胞入侵或逃逸的可能性很小？在病理生理学中，某些细胞群是否会变得像液体一样，并允许细胞旁渗漏、转化、入侵或细胞逃逸，因为它们变得不受阻碍？为了回答这些问题，我们的跨学科团队将在特征良好的内皮和上皮单层系统中测试干扰假设。为了测试干扰假说的适用性，我们将研究EMT前后四种特征良好的稳定细胞系。这些实验研究将通过我们提议开发的一种使能新技术：单层应力显微镜。

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). PUBLIC HEALTH RELEVANCE: Recent technical and conceptual advances from our team1-13 lead to the suggestion that mechanics of the cellular monolayer in the lung, and in other organ systems as well, may be dominated by a change of state called the jamming transition. This new perspective leads logically to important new questions. In normal physiology, for example, do cellular monolayers tend to form solidlike aggregated sheets -with excellent barrier function and with little possibility of cell invasion or escape- because constituent cells are jammed? In pathophysiology, do certain cell populations become fluidlike and permissive of paracellular leak, transformation, invasion or cell escape because they become unjammed? To answer these questions, our interdisciplinary team will test the jamming hypothesis in well-characterized endothelial and epithelial monolayer systems. And to test the limits of applicability of the jamming hypothesis, we will study four well-characterized stable cell lines pre- and post-EMT. These experimental studies will be made possible by an enabling new technology that we pro- pose to develop: Monolayer Stress Microscopy.