Probing the Active Tensioning Response Under Sustained Strain in Epithelial Cells

This award supports a research program to study how epithelial cells respond to prolonged mechanical load. Epithelial cells are a single layer or a few layers of cells lining the surfaces of our tissues, providing a protective barrier between our body and the external environment. As part of their normal function, they experience long-lasting mechanical loads at different magnitudes and rates. To maintain a healthy stress level, they must develop mechanisms to adapt to these sustained loads. Indeed, epithelial cells often perform stress relaxation which can mitigate the risk of tissue fracture. However, when loads are too large, occur too quickly, or last too long, stress relaxation may lead to dangerously large deformations that compromise cellular homeostasis. To support a healthy shape, cells may need to actively pull back, like muscle contraction, to reduce deformation. This phenomenon is referred to as stiffening or tensioning. Currently, observations and understanding of these tensioning processes are limited. This project will study this phenomenon in epithelial cells by looking into their stress responses under load and uncovering the mechanisms that activate their tensioning responses. How cells adapt to their tensioned environments and adjust their stress levels play a significant role in tissue development and disease. Thus, obtaining this knowledge will be critical in advancing our understanding of various disease pathologies and therapeutics in the epithelia. The specific goal of the research is to characterize the tensioning phenomena in epithelial cells in response to sustained strain and to delineate the underlying mechanosensing mechanism that mediates this response. The central hypothesis is that tensioning is a universal stress response mechanism in epithelial cells, as a protection mechanism against environmental strain, and that this active tensioning is mediated by mechanosensing molecules at the cell-extracellular matrix (ECM) interface but not at the cell-cell interface. By subjecting single cells and cell pairs to defined strains at various rates and recording their stress evolution at the cell-cell and cell-ECM interfaces, the project seeks to provide a comprehensive characterization of their tensioning dynamics and uncover the mechanosensors that trigger the tensioning response. Collectively, the study looks to generate new knowledge on how epithelial cells control their shape and dynamics under sustained load. The technique that will be developed in this project to simultaneously evaluate traction stress and intercellular stress can also be adopted in other mechanobiology studies. 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.