Epithelial Cell Mechanobiology in Mechanically Heterogeneous Microenvironments

项目总结 在发育和疾病期间，上皮细胞可以集体迁移，无论是否经历上皮- 间充质转化(EMT)，通过非均质基质，实现基本过程，如 分支形态发生、纤维化和肿瘤侵袭。我们已经证明，细胞外基质(ECM) 超出当前ECM硬度的特性，如约束和过去的ECM硬度，可以从根本上 改变上皮细胞的反应。通过一系列项目，结合实验和模拟，这 该提案将揭示新模式在不同刚度和强度的矩阵中的集体细胞行为 地形。我们将测量上皮细胞在基底膜缺陷周围的EMT和迁移。 (BM)类矩阵，确定缺陷诱导的EMT造成的3D入侵，构建计算模型以 了解依赖于速率的EMT进化，并从药物上干扰BM的降解。我们还将评估 上皮细胞是否能够深入其基质并改变基于远距离僵硬的反应 矩阵。在另一个项目中，我们将研究细胞片如何在类似3D的受限环境中迁移 可调的硬度和地形。我们将把核形状与细胞骨架重组联系起来，以理解 细胞如何适应过去和现在矩阵的不同硬度。这些项目的成果将使新的 对残留的基质异质性的上皮细胞反应的基本了解 尚未探索，并可能揭示纤维化和癌症等疾病的新靶点。

PROJECT SUMMARY During development and disease, epithelial cells can migrate collectively, with or without undergoing epithelial- mesenchymal transition (EMT), through heterogeneous matrices, enabling fundamental processes such as branching morphogenesis, fibrosis, and tumor invasion. We have shown that extracellular matrix (ECM) properties beyond the current ECM stiffness, such as confinement and past ECM stiffness, can fundamentally alter epithelial responses. Through a collection of projects, combining experiments and simulations, this proposal will reveal new modes collective cell behaviors in matrices of heterogeneous stiffness and topography. We will measure EMT and migration of epithelial cells around defects in a basement membrane (BM)-like matrix, determine 3D invasion due to defect-induced EMT, build a computational model to understand rate-dependent EMT evolution, and pharmacologically disrupt BM degradation. We will also assess whether the epithelial cells can sense deeply into their matrix and alter responses based on distant stiffening of the matrix. In another project, we will investigate how cell sheets migrate in 3D-like confined environments of tunable stiffness and topography. We will connect nuclear shape with cytoskeletal reorganization to understand how cells adapt to distinct stiffnesses of past and present matrices. Outcomes of these projects will enable new fundamental understanding of epithelial cell responses to matrix heterogeneities that have remained unexplored and could reveal novel targets for diseases such as fibrosis and cancer.