Mechanics of Monolayer Migration

单层迁移的力学

• 批准号: 8253706
• 负责人: Jeffrey J Fredberg
• 金额: $ 61.83万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-06 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8253706
• 关键词: Adhesions; Adhesives; Asthma; Attention; Biological Models; Breathing; Cell Adhesion Molecules; Cell Communication; Cell Line; Cells; Chemicals; Chemotaxis; Chronic Obstructive Airway Disease; Coffee; Complex; Comprehension; Data; Duct (organ) structure; Epithelial; Event; Fibrosis; Functional disorder; Goals; Growth; Heterogeneity; Human; Immigration; Individual; Lead; Libraries; Link; Logic; Lung; Measures; Mechanical Stress; Mechanical ventilation; Mechanics; Mesenchymal; Microscopy; Molecular; Morphogenesis; Motion; Natural regeneration; Phase; Physiology; Play; Population; Preclinical Drug Evaluation; Role; Source; Staging; Stress; Suggestion; System; Testing; base; bean; body system; cancer cell; cell motility; epithelial to mesenchymal transition; injury and repair; lung development; men who have sex with men; migration; molecular scale; monolayer; new technology; novel; prototype; public health relevance; repaired; research study; stable cell line; stem cell biology; tumor progression

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.

描述（由申请人提供）：肺中的细胞通常不是作为个体实体迁移，而是作为集合片、导管、线或簇迁移。但每个细胞如何协调其与邻近细胞的迁移仍然无法完全理解。我们在这里提出一个假设，即协调细胞迁移的一个被忽视但仍然重要的特征是每个组成细胞都可能受到最近邻居的物理约束（堵塞）。干扰假说看似简单，但却做出了令人惊讶、复杂且可测试的先验机械预测。它预测：1）集成单层内的细胞如果没有其直接邻居的协作运动就无法迁移； 2）这种协作性阻碍了系统的动态，并且是通过自发出现的显着异质的力链来实现的，这些力链在组织的多个尺度上波及系统； 3）减少粘附相互作用，或减少压缩应力，或增加呼吸和机械通气中发生的潮汐变形，所有这些都有助于促进细胞解干扰和解聚，并且都由统一的干扰相图来描述。使用独特的实验平台原型——单层应力显微镜——我们获得了支持这一新颖物理图片的初步数据。如果它被证明具有预测能力，那么这一假设将把上皮和内皮单层生理学以及修复、屏障功能、纤维化和上皮-间质转化（EMT）中集体片迁移的不同方面汇集在一个机制标题下。 ）。 公共卫生相关性：我们团队 1-13 最近的技术和概念进展表明，肺部以及其他器官系统中的细胞单层力学可能由称为干扰转换的状态变化主导。这种新观点从逻辑上引出了重要的新问题。例如，在正常生理学中，细胞单层是否会因为组成细胞被堵塞而倾向于形成固体状聚集片——具有优异的屏障功能并且细胞入侵或逃逸的可能性很小？在病理生理学中，某些细胞群是否会因为不受堵塞而变得像流体一样并允许细胞旁渗漏、转化、入侵或细胞逃逸？为了回答这些问题，我们的跨学科团队将在充分表征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极限，我们将研究 EMT 前后的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项新技术得以实现：单层应力显微镜。