The combined role of cellular force dynamics and extracellular matrix mechanical properties in driving angiogenesis

血管生成是一个复杂的过程，生化和机械信号调控内皮细胞的增殖和迁移。近年来，我们在对力在内皮细胞(EC)中的作用的理解上取得了一些进展。细胞的伸缩性现在被认为是一种重要的细胞属性，它影响细胞的正常和病理过程，包括细胞黏附和迁移。细胞的收缩能力反过来又受到细胞外基质(ECM)的机械特性的影响。尽管对生物系统中产生的力进行了深入的研究，但力与动态机械特性之间的调节关系实际上仍然是未知的。这在组织工程学中是一个持续存在的问题，因为它影响了我们准确重建工程化疾病模型或控制可植入支架的新生血管过程的能力。 目的：本研究计划将利用我们在机械生物学和生物光子学方面的背景，研究血管生成过程中三维微环境的物理特性与细胞力生成之间的动态相互作用。该计划将解决以下主要目标：(1)研究EC力产生的时间动力学和相关的分子控制；(2)探索离散应变在工程胶原支架中的传播及其对EC行为的影响。 影响：我们的工作将提供关于血管生成过程中分子控制、细胞力和ECM机械性能之间的功能联系和关系的新数据，可用于设计更好的组织工程支架。此外，考虑到细胞力和ECM力学之间的关系并不是ECs独有的，这个项目将在机械生物学领域产生深远的影响，并为我们理解力在生理过程中的作用提供关键的见解。此外，这项工作利用了一个在加拿大独一无二的新工具，唯一的其他类似系统是在范德比尔特大学。通过增加我们在使用QPOL显微镜回答生物学问题方面的专业知识，我们的目标是使技术转移到组织工程师以及癌症和心血管研究人员。总体而言，该研究计划将通过提供一个高度跨学科的环境，帮助高素质人才的培训，让他们学习生物技术领域非常受欢迎的生物工程、物理和细胞生物学的尖端技术。

Angiogenesis is a complex process where biochemical and mechanical signals regulate endothelial cell proliferation and migration. Recent years have seen several advances in our understanding of the role of forces in endothelial cells (EC). Cellular contractility is now fully appreciated as a crucial cell property that influences cell behaviors involved in both normal and pathological processes, including cell adhesion and migration. Cell contractility is known to be in turn influenced by the mechanical properties of the extracellular matrix (ECM). Despite intensive efforts to characterize the forces generated in biological systems, the regulatory relationships between forces and dynamic mechanical properties remain virtually unknown. This is an ongoing problematic in tissue engineering since it affects our ability to accurately recreate engineered disease models or control the neovascularization process of implantable scaffolds. Objectives: This research program will use our background in mechanobiology and biophotonics to investigate the dynamic interplay between the physical properties of the 3D microenvironment and cell force generation during angiogenesis. The program will address the following main goals: (1) investigate the temporal dynamics of EC force generation and associated molecular controls, and (2) probe discrete strain propagation within engineered collagen scaffolds and its influence on EC behavior. Impact: Our work will provide new data on the functional link and relationship between molecular controls, cell forces, and ECM mechanical properties during angiogenesis that can be used to design better tissue engineered scaffolds. Furthermore, considering that the relationship between cell forces and ECM mechanics is not unique to ECs, this project will have far reaching impacts in the field of mechanobiology and provide critical insights in our understanding of the role of forces in physiological processes. In addition, this work leverages a novel tool that would be unique in Canada, with the only other similar system being at Vanderbilt University. By increasing our expertise in the use of QPOL microscopy to answer biological questions, we aim to enable technological transfer toward tissue engineers as well as cancer and cardiovascular researchers. Overall, this research program will contribute to the training of highly qualified personnel by providing a highly interdisciplinary environment where they will learn cutting edge techniques in bioengineering, physics, and cellular biology that are highly sought after in the field of biotechnology.