Collaborative Research: DMS/NIGMS 1: Simulating cell migration with a multi-scale 3D model fed by intracellular tension sensing measurements

这是印第安纳大学、印第安纳波利斯大学和普渡大学的合作项目。细胞迁移在许多环境中起着重要作用，包括癌症转移、伤口愈合和免疫反应。例如，乳腺癌细胞迁移被认为是转移性骨或肺肿瘤的主要风险因素，伤口愈合中的成纤维细胞迁移在糖尿病和坏死性小肠结肠炎(危及生命的肠道伤口，影响10%的早产儿)中起作用。该项目旨在了解细胞迁移的内在属性，即细胞内力如何响应周围、外部环境的属性并驱动细胞迁移。为了做到这一点，PI将开发一个新的迁移细胞的数学模型。该模型将细胞迁移和细胞属性的现有知识与一种可以测量亚细胞力的成像方法结合在一起。该模型将产生整个电池的力信息，而不仅仅是测量位置的力信息。结合这一模型进行适当的统计分析，将有助于确定外部环境如何通过内部亚细胞力量的产生来影响迁移。这反过来将帮助我们更好地了解如何抑制(例如癌症)或促进(例如伤口愈合)细胞迁移，以改善患者的预后。该项目将指导和培训来自多个学科的毕业生，通过印第安纳大学印第安纳波利斯大学的NSF-DMS REU计划缺乏研究机会的机构的本科生，以及通过美国化学协会SEED/STEM项目指导和培训社会经济贫困的高中生。计划包括通过在几个会议上的演讲和小型专题讨论会、开放获取的出版物、YouTube帖子、课堂单元、当地社区演讲(Science On Tap)和STEM青年充实暑期计划，为代表不足的高中生提供服务。细胞迁移是由细胞内力驱动的，但主要受细胞外特性和扰动的影响。为了了解细胞外特性如何决定指导细胞迁移的内力，PI计划实现三个具体目标：1)开发一个模型，将实验测量的细胞内张力整合在一起，并使用它们来建立整个细胞的力结构；2)使用该模型和实验测量来确定哪些亚细胞组件在细胞迁移中起主要作用；以及3)使用建模和实验来了解细胞内力和迁移对外部特性的响应。通过这种方法，PI将能够识别几条主要的路径(从外部属性到亚细胞组件再到定向运动)，外部属性通过这些路径使用亚细胞力来指导迁移。在该模型中，细胞将由一组相互连接的粘弹性弹簧来表示，该弹簧模拟薄膜和其他亚细胞组件。流动将使用一种新的格子-玻尔兹曼方法来模拟稳态的斯托克斯流动。流体-结构相互作用将使用浸没边界方法来模拟。通过实验对模型进行了标定和验证。内张力实验将使用成像方法和各种分子张力传感器来捕捉细胞内的力情况，特别是在焦点粘连、细胞骨架连接和核膜上。外部环境的改变将包括细胞外基质硬度、趋化梯度和流动特性。相关性、敏感性和主成分分析将被用来确定潜在的迁徙路径。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

This is a Collaborative Project between Indiana University Indianapolis and Purdue University. Cell migration plays a major role in many settings including cancer metastasis, wound healing, and the immune response. For example, breast cancer cell migration is considered a major risk factor for metastatic bone or lung tumors and fibroblast migration in wound healing has roles in diabetes and necrotizing enterocolitis (life-threatening intestinal wounds that affect 10% of premature babies). This project aims to understand the intrinsic properties of cell migration, i.e., how internal forces of a cell respond to the properties of the surrounding, external environment and drive cell migration. To do this, The PIs will develop a novel mathematical model of a migrating cell. The model combines pre-existing knowledge of cell migration and cell properties with an imaging method that can measure subcellular forces. The model will yield force information throughout the cell, not just at the measurement locations. Accompanying that model with appropriate statistical analysis will help identify how the external environment can effect migration via internal subcellular force generation. This, in turn, will help us better understand how to inhibit (e.g. cancer) or promote (e.g. wound healing) cell migration in order to improve patient outcomes. The project will mentor and train graduates from multiple disciplines, undergraduates from institutions lacking research opportunities through Indiana University Indianapolis’s NSF-DMS REU program, and socioeconomically disadvantaged high schoolers through the American Chemical Society Project SEED/STEM. Plans include outreach via presentations and minisymposia at several conferences, open-access publications, YouTube postings, in-class modules, local community presentations (Science on Tap), and the STEM Youth Enrichment Summer program for underrepresented high schoolers. Cell migration is driven by its intracellular forces but is mainly directed by extracellular properties and perturbations. To understand how extracellular properties determine internal forces to direct cell migration, the PIs plan to accomplish three specific aims: 1) Develop a model that integrates experimentally measured intracellular tensions and uses them to establish a force architecture throughout the cell, 2) Use that model and the experimental measurements to identify which subcellular components play major roles in cell migration, and 3) Use modeling and experiments to understand the response of internal forces and migration of the cell to the external properties. Through this approach the PIs will be able to identify several primary pathways (external properties to subcellular components to directed motion) by which external properties use subcellular forces to direct migration. In the model, the cell will be represented by a set of interconnected viscoelastic springs modeling the membrane and other subcellular components. The flow will be modeled using a novel lattice-Boltzmann approach for steady-state Stokes flow. Fluid-structure interaction will be modeled using the immersed boundary method. The model will be calibrated and validated using the experiments. The internal tension experiments will use imaging methods and various molecular tension sensors to capture the force landscape within a cell, particularly at focal adhesions, cytoskeletal junctures, and the nuclear envelope. The external environmental alteration will include the extracellular matrix stiffness, chemotactic gradient, and flow properties. Correlation, sensitivity, and principal component analyses will be used to identify potential migratory pathways.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.