Mechanical homeostasis - An Emergent Property of the Multi-Tiered Structure of Living Cells and Tissues

Tissues in the body can be compressed or stretched by external and internal mechanical forces, such as the swelling of a region of tissue in contact with another. Abnormally large mechanical forces can lead to significant buildup of stress in the tissue that can damage individual cells and alter their gene expression to perhaps lead to abnormalities in function. However, when a cell is compressed, causing its cell nucleus to compress, nuclear blebs, or protrusions of the nucleoskeletal shell surrounding the genetic material, may form. These blebs can potentially relieve stress build up in the cell nucleus so that it can continue to function normally. Such blebs can even rupture to further relieve stress. The ability of cells, whether individually or in groups, to handle such forces while also maintaining their functionality is known as mechanical homeostasis. Understanding how these physical forces transmit between and within cells and how cells respond and adapt to these forces over time is key to understanding this functional robustness. And yet, due to the interactions at the cell nuclear scale, the cell scale, and the tissue scale, the process is complex, which, up to now, has limited our understanding. To address the multi-tiered chain of complexity underlying mechanical homeostasis, in this award the PIs will build on their prior work at the cell nuclear scale, the cell scale, and the tissue scale to create a comprehensive, multi-tiered physics framework based on experiments and computational models to predict how cell nuclei maintain function under extreme mechanical stress. Specifically, the PIs will focus on how cell compression deforms and damages the nucleus and triggers adaptation mechanisms in the nuceloskeletal shell, such the rehealing of the shell after blebbing and rupture. They will also investigate how whole-cell compression impacts how the genetic material inside the nucleus re-organizes and adapts. Finally, the PIs will explore how tissue-level forces influence chromatin organization and identify new adaptation strategies. With this exploration, the proposal aims to create a universal physics model to explain how cells and tissues adapt to mechanical forces, thereby contributing to the fields of quantitative biology and mechanobiology through the lens of physics. The PIs will also work to promote interdisciplinary education at the university level. Collaborating with creative writing professors at Syracuse University, the project will involve biophysics undergraduates and creative writing students in joint activities. This will include lectures on biophysics in creative writing classes, lectures on writing in biophysics courses, and collaborative writing projects. This initiative aims to improve communication skills, foster creativity, and break down barriers between the disciplines. 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.