Influence of Hydraulic Resistance on the Osmotic Engine Model of Cell Migration

水力阻力对细胞迁移渗透发动机模型的影响

• 批准号: 10457983
• 负责人: Konstantinos Konstantopoulos
• 金额: $ 37.21万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-16 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10457983
• 关键词: 3-Dimensional; Actins; Address; Applications Grants; Architecture; Automobile Driving; Biological Process; Cancer Biology; Cell Energetics; Cell Shape; Cell membrane; Cell model; Cell surface; Cells; Cellular biology; Collagen; Complex; Computing Methodologies; Confined Spaces; Cytoplasm; Cytoskeleton; Data; Dependence; Developmental Biology; Disease Progression; Embryonic Development; Energy Metabolism; Environment; Event; Exhibits; Extracellular Matrix; Geometry; Hydrogels; Image; Ion Channel; Ion Transport; Ions; Length; Liquid substance; Measures; Mediating; Membrane; Methods; Methylcellulose; Modeling; Molecular; Molecular Biology; Myosin ATPase; Neoplasm Metastasis; Permeability; Phase; Physiological; Porosity; Process; Research; Resistance; Role; Seminal; Signal Transduction; Speed; Technology; Theoretical model; Tissues; Translating; Viscosity; Water; Work; active control; base; cell motility; experience; experimental study; extracellular; fluid flow; in vivo; interdisciplinary approach; mathematical model; microdevice; migration; polarized cell; polymerization; pressure; response; role model; tool; water flow

Summary Understanding the mechanisms of cell migration is a fundamental question in cell, developmental and cancer biology. Decades of research has shown that the molecular underpinnings of cell migration are complex and the physical mechanisms driving migration are diverse. We have shown that depending on the local microenvironment, cell migration can be driven by actin polymerization as well as an osmotic gradient-driven water flux external to the cell. This so-called osmotic engine model (OEM) is prominent when cells are in tightly confined spaces. In vivo, cells migrate within diverse microenvironments, ranging from dense 3D extracellular matrices to narrow microchannels present in tissue, to complex somatic spaces with various kinds of physical obstacles. An open and un-addressed question is what are the important variables that dictate the relative contribution of actin polymerization-driven and water-based migratory mechanisms in diverse microenvironments. Recent data reveal that the degree of cell confinement and the hydraulic resistance experienced by cells represent key factors in determining the mechanisms driving cell movement. Theoretical modeling utilizing a two-phase model of the cell cytoplasm also predicts that the hydraulic resistance experienced by the cell dictates the relative contribution of water flow/OEM to the observed cell speed. Mounting experimental evidence also suggests that cells can sense hydraulic pressure and modulate cell migration mechanisms. In this grant application, we propose to develop an integrated modeling and experimental approach to delineate the relative contributions of the actin-phase and the water-phase to cell migration as a function of external hydraulic resistance. In Aim 1, we propose to directly quantify how hydraulic resistance influences cell migration speeds by examining cells both in 2D in media with added methylcellulose, which increases medium viscosity, and inside confining microchannels of varying channel length, which also modulate hydraulic resistance. The roles of key ion channels and transporters that are involved in setting up water flux and the energetics of migration will be explored experimentally and theoretically. We will also identify the key mechanosensitive ion channels responsible for sensing hydraulic resistance. In Aim 2, we will explore the interplay between actin polymerization, membrane tension changes and OEM in environments of elevated hydraulic resistance. We will also extend the two-phase theoretical model of cell migration in include membrane tension and flows. Since cell migration speeds may depend on cell shape, in Aim 3, we will develop a general two-phase moving boundary method to compute cell movement for arbitrary cell shapes. We will also explore how OEM influences cell migration in dense vs more porous 3D collagen matrices, which exhibit different hydraulic resistances. Taken together, we will discover the mechanisms behind the counterintuitive observation of faster migration in high hydraulic resistance environments using a multidisciplinary approach, involving state-of-the-art microdevices, imaging, molecular biology tools along with mathematical modeling.

概括 了解细胞迁移的机制是细胞，发育和癌症中的一个基本问题 生物学。数十年的研究表明，细胞迁移的分子基础很复杂， 驱动迁移的物理机制是多种多样的。我们已经表明，取决于当地 微环境，细胞迁移可以通过肌动蛋白聚合以及渗透梯度驱动的驱动 电池外部的水通量。当细胞紧密地处于细胞时，这种所谓的渗透发动机模型（OEM）是突出的 狭窄的空间。在体内，细胞在各种微环境内迁移，范围从密集的3D细胞外迁移 矩阵到组织中存在的狭窄微通道，到具有各种物理的复杂体细胞空间 障碍。一个开放且未解决的问题是决定亲戚的重要变量 肌动蛋白聚合驱动和水基迁移机制的贡献 微环境。最近的数据表明，细胞限制程度和液压抗性 细胞经历代表了确定驱动细胞运动的机制的关键因素。理论 使用细胞质的两相模型进行建模，还预测了液压抗性 细胞经历决定了水流/OEM对观察到的细胞速度的相对贡献。 安装实验证据还表明，细胞可以感觉到液压压力并调节细胞 迁移机制。在此赠款应用程序中，我们建议开发一个集成的建模和 描述肌动蛋白期和水相对细胞的相对贡献的实验方法 迁移是外部液压阻力的函数。在AIM 1中，我们建议直接量化液压的方式 抗性通过在培养基中使用甲基纤维素添加的培养基中的2D中的细胞来影响细胞迁移速度， 这会增加中等粘度，并在限制各种通道长度的微通道内部，这也是 调节液压电阻。关键离子通道和转运蛋白在设置中的作用 水通量和迁移的能量将在实验和理论上进行探索。我们还将确定 关键机械敏感的离子通道负责感测液压电阻。在AIM 2中，我们将探索 肌动蛋白聚合，膜张力的变化和OEM之间的相互作用在升高环境中 液压抗性。我们还将扩展细胞迁移的两相理论模型包括 膜张力和流动。由于细胞迁移速度可能取决于细胞形状，因此在AIM 3中，我们将发展 一般的两相移动边界方法，用于计算单元格的细胞运动。我们也会 探索OEM如何影响细胞迁移，与更多的多孔3D胶原蛋白矩阵（展示） 不同的液压电阻。综上所述，我们将发现违反直觉背后的机制 使用多学科方法观察高液压抗性环境中更快的迁移， 涉及最先进的微论门，成像，分子生物学工具以及数学建模。