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 了解细胞迁移机制是细胞、发育和癌症领域的一个基本问题 生物学。数十年的研究表明，细胞迁移的分子基础非常复杂， 驱动移民的物理机制是多种多样的。我们已经证明，根据当地情况 在微环境中，细胞迁移可以由肌动蛋白聚合以及渗透梯度驱动驱动 细胞外部的水通量。当细胞紧密结合时，这种所谓的渗透引擎模型（OEM）就很突出。 密闭空间。在体内，细胞在不同的微环境中迁移，从致密的 3D 细胞外 矩阵到组织中存在的狭窄微通道，到具有各种物理性质的复杂体细胞空间 障碍。一个开放且未解决的问题是，决定相对值的重要变量是什么？ 肌动蛋白聚合驱动和水基迁移机制在不同领域的贡献 微环境。最近的数据表明，细胞限制程度和水力阻力 细胞所经历的经历代表了决定驱动细胞运动的机制的关键因素。理论 利用细胞质的两相模型进行建模还预测了液压阻力 细胞所经历的情况决定了水流/OEM 对观察到的细胞速度的相对贡献。 越来越多的实验证据还表明，细胞可以感知液压并调节细胞 迁移机制。在本次拨款申请中，我们建议开发一个集成建模和 描述肌动蛋白相和水相对细胞的相对贡献的实验方法 迁移作为外部液压阻力的函数。在目标 1 中，我们建议直接量化液压 通过在添加甲基纤维素的培养基中以二维方式检查细胞，阻力影响细胞迁移速度， 这增加了介质粘度，并且内部限制了不同通道长度的微通道，这也 调节液压阻力。参与建立的关键离子通道和转运蛋白的作用 水通量和迁移能量学将通过实验和理论进行探索。我们还将确定 负责传感液压阻力的关键机械敏感离子通道。在目标 2 中，我们将探索 在升高的环境中肌动蛋白聚合、膜张力变化和 OEM 之间的相互作用 液压阻力。我们还将扩展细胞迁移的两相理论模型，包括 膜张力和流量。由于细胞迁移速度可能取决于细胞形状，因此在目标 3 中，我们将开发 用于计算任意细胞形状的细胞运动的通用两相移动边界方法。我们还将 探索 OEM 如何影响致密与多孔 3D 胶原基质中的细胞迁移，其中表现出 不同的水力阻力。综上所述，我们将发现反直觉背后的机制 使用多学科方法观察高水力阻力环境中的更快迁移， 涉及最先进的微型设备、成像、分子生物学工具以及数学建模。