Multi-cue Guidance of Mesenchymal Cell Migration

间充质细胞迁移的多线索引导

• 批准号: 10185787
• 负责人: Jason M. Haugh
• 金额: $ 28.88万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10185787
• 关键词: Actins; Affect; Biological Assay; Cardiovascular Diseases; Cardiovascular system; Cells; Cellular biology; Chemicals; Chemotactic Factors; Chemotaxis; Complex; Cues; Cytoskeleton; Disease; Disseminated Malignant Neoplasm; Elements; Engineering; Extracellular Matrix; F-Actin; Feedback; Fibroblasts; Fibrosis; Generations; Image Analysis; Immobilization; Integrins; Leukocytes; Ligands; Location; Mediating; Mesenchymal; Microfluidics; Molecular; Movement; Myosin Regulatory Light Chains; Neoplasm Metastasis; Nonmuscle Myosin Type IIA; Pathologic; Pathway interactions; Phospholipase C; Phosphorylation; Physiological; Physiological Processes; Platelet-Derived Growth Factor; Play; Process; Protein Kinase C; Regulation; Regulatory Pathway; Role; Shapes; Signal Pathway; Signal Transduction; Signaling Protein; Surface; Testing; Time; Tissues; Variant; Work; cell behavior; cell motility; combinatorial; density; in vivo; interdisciplinary approach; link protein; microscopic imaging; migration; non-muscle myosin; polymerization; synergism; tumor; wound; wound healing

SUMMARY Cells in a variety of contexts migrate towards soluble chemical cues in a process known as chemotaxis. Despite nearly a century of study, the mechanistic underpinnings of chemotaxis remain incompletely understood. Spatial gradients of platelet-derived growth factor (PDGF) and other chemoattractants direct the movements of mesenchymal cells in tissues to coordinate and accelerate physiologically important processes such as wound healing, and mesenchymal chemotaxis has been implicated in pathological conditions such as cardiovascular and fibrotic diseases. Despite the central role that fibroblasts and other mesenchymal cells play in wound healing and other disease processes such as metastatic cancer and fibrosis, a rigorous understanding of mechanisms governing the directed migration of mesenchymal cells is only recently emerging. To advance further, a quantitative, integrative approach is required. Specifically, it is necessary to elucidate how the central regulatory pathways network with others and how they are coordinated with respect to subcellular location and time to affect cell behavior. In the context of directed mesenchymal cell migration, another layer of complexity is the variation of gradient conditions (midpoint concentration/surface density and steepness). Enabled by new engineering advances, we are poised to tackle these new questions related to chemotaxis and haptotaxis and to their combinatorial influence in multi-cue settings. Our Specific Aims are as follows: Aim 1: Decoding the dynamics of multiple signaling axes that shape mesenchymal chemotaxis. We will test the hypothesis that protrusion dynamics are governed by the metastable push/pull of Arp2/3 complex and NMII activities, which are insufficiently biased by a chemotactic gradient. With stable polarization of active PKC in the most-up-gradient protrusion, the inactivation of NMII there provides a ‘port in the storm’ for pro-Arp2/3 signaling to mediate more productive protrusion. Aim 2: Probing the dynamics of haptotactic sensing and signal amplification. We hypothesize that differential integrin engagement on ECM gradients drives significant cell migration bias through feedback amplification of the pro-Arp2/3 signaling axis. If so, it would imply that haptotactic gradients are able to bias pro-Arp2/3 signaling in mesenchymal cells to an extent that chemotactic gradients cannot. Aim 3: Defining gradient synergy and prioritization in multi-cue scenarios. Despite the relevance for guidance of mesenchymal cells in vivo, it is completely unknown how cells respond to co-presentation of the two gradient types in a controlled setting. Considering how chemotaxis and haptotaxis affect dynamic regulation of the actin cytoskeleton in fibroblasts, we hypothesize that the two gradients synergize when presented in a parallel orientation. By presenting the gradients in an antiparallel or orthogonal orientation, we will determine how cells prioritize the two types of cues.

概括 各种环境下的细胞都会向可溶性化学信号迁移，这一过程称为趋化性。 尽管经过近一个世纪的研究，趋化性的机制基础仍然不完全 了解血小板衍生生长因子（PDGF）和其他化学引诱剂的空间梯度。 组织中间充质细胞的运动协调和加速具有重要的生理意义 伤口愈合和间质趋化等过程与病理学有关 尽管成纤维细胞和其他疾病起着核心作用。 间充质细胞在伤口愈合和其他疾病过程中发挥作用，例如转移性癌症和 纤维化，严格理解控制间充质细胞定向迁移的机制 为进一步推进，需要采用定量、综合的方法。 具体来说，有必要阐明中央监管途径如何与其他途径联网以及如何 它们在亚细胞位置和时间方面进行协调以影响细胞行为。 定向间充质细胞迁移，另一层复杂性是梯度条件的变化 （中点浓度/表面密度和陡度）。 准备好解决这些与趋化性和趋触性及其组合相关的新问题 我们的具体目标如下： 目标 1：解码塑造间充质趋化性的多个信号轴的动态。 我们将测试突出动力学受 Arp2/3 的亚稳态推/拉控制的假设 复合物和 NMII 活性，趋化梯度的偏差不足。 最上梯度突起中活性 PKC 的极化，那里 NMII 的失活提供了 pro-Arp2/3 信号的“风暴中的端口”可以调节更有效的突出。 目标 2：探索触觉传感和信号放大的动态。 ECM 梯度上整合素的差异参与通过反馈驱动显着的细胞迁移偏差 pro-Arp2/3 信号轴的放大 如果是这样，则意味着趋触梯度能够放大 使间充质细胞中的 pro-Arp2/3 信号产生偏向，达到趋化梯度无法达到的程度。 目标 3：定义多线索场景中的梯度协同和优先级，尽管具有相关性。 对于体内间充质细胞的指导，细胞如何响应共呈现是完全未知的 考虑趋化性和趋触性如何影响受控环境中的两种梯度类型。 成纤维细胞中肌动蛋白细胞骨架的动态调节，我们发现两个梯度 以平行方向呈现时协同作用 通过以反平行或反向呈现梯度。 正交方向，我们将确定细胞如何优先考虑两种类型的线索。