ERI: Multi-Scale Modeling of Cell-Matrix Mechanical Interactions in Endothelial Cell Network Assembly

这项工程研究启动（ERI）奖将支持有关哺乳动物细胞如何组织成功能性多细胞结构的研究。具体来说，将揭示细胞如何通过物理线索组织起来。重点将放在自组织的蜂窝网络上。这些网络已知发生在血管形成之前。它们需要特殊的特性来成功地运输营养物质和氧气。如果条件合适，组织可以在合成环境中被改造。这些条件包括细胞、材料和化学因素的组合。通过对细胞网络的机械操作来改造这些组织也有效果。更好地理解这些机制意味着受损组织最终可以被修复和替换。这项研究的结果将有助于科学认识和国民健康。多学科研究方法将与教育活动相结合。这些活动将向学生介绍生命科学中的定量方法。该项目还将有助于在加州服务不足的中央山谷地区招募、留住和培训科学和工程领域的学生。该研究将使用数学建模和基于主体的计算来识别由细胞外基质弹性变形介导的细胞间相互作用产生的多细胞结构。细胞可以施加收缩牵引力使其物质环境变形或重组。建模将结合单个细胞的运动和细胞间的机械相互作用，通过它们相互变形的基底。基材将在多个尺度上作为线性弹性连续体以及离散的纤维介质进行建模。在模拟中获得的模型细胞网络将被定量分析，以获得与运输功能相关的关键指标，如连接、分支和环路的数量及其空间覆盖。这些定量测量将预测细胞网络结构和功能如何依赖于衬底力学性能。这些结果将与软基质上血管细胞网络的现有实验数据分析进行比较。在这个项目中开发的模型可以在未来扩展到描述其他细胞类型在其他培养几何形状中的自组装，包括三维组装。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

This Engineering Research Initiation (ERI) award will support research about how mammalian cells organize into functional multicellular structures. Specifically, how cells organize through physical cues will be revealed. The focus will be on self-organized cell networks. These networks are known to occur prior to blood vessel formation. They require specific properties to successfully transport nutrients and oxygen. Tissue can be engineered in synthetic environments if the conditions are right. Those conditions include a combination of cells, materials, and chemical factors. Engineering these tissues by mechanical manipulations of the cell network can also have effects. Better understanding these mechanisms means that damaged tissues can ultimately be restored and replaced. The results of this research will contribute to both scientific understanding and national health. The multidisciplinary research approach will be combined with educational activities. These activities will introduce students to quantitative approaches in the life sciences. This project will also contribute to the recruitment, retention, and training of students in science and engineering fields in the underserved Central Valley region of California. The research will use mathematical modeling and agent-based computation to identify the multicellular structures that result from intercellular interactions mediated by the elastic deformations of the extracellular substrate. A cell can exert contractile traction forces to deform or restructure its material environment. The modeling will combine individual cell motility with cell-cell mechanical interactions through their mutual deformations of the substrate. The substrate will be modeled at multiple scales as a linear elastic continuum as well as a discrete, fibrous medium. The model cell networks obtained in simulation will be analyzed quantitatively to obtain crucial metrics related to transport functions such as the number of junctions, branches and loops, and their space coverage. These quantitative measures will predict how the cell network structure and function depend on substrate mechanical properties. These results will be compared with analysis of available experimental data on vascular cell networks on soft substrates. The modeling developed during this project can be extended in the future to describe the self-assembly of other cell types in other culture geometries including three-dimensional assemblies.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.