Effects of Stretch and Intercellular Force Transmission on Tensional Homeostasis in Multicellular Clusters

Trustees Of Boston University, Boston

Investigators

Abstract

The ability of living cells to maintain their internal mechanical stress in response to external disturbances is essential for normal physiological functions of cells and tissues and for a protection against various diseases. This is known as tensional homeostasis. Breakdown of tensional homeostasis is the hallmark of most advanced solid cancers (carcinomas), as well as of stiffening of the arteries (atherosclerosis) and clot formation (thrombosis). While physical interactions between cells appear to be fundamental to tensional homeostasis, important questions remain. First, it is not known how the transmission of forces between cells impacts tensional homeostasis. Second, there is little understanding of how cells respond to external changes in their mechanical environment (e.g., mechanical stretch) after having initially achieved a steady state. In order to address these questions, this project will advance and apply a biomechanical imaging computational platform. The fundamental questions that can be answered using this technique will improve basic understanding of how cells respond to their mechanical environment. The biomechanical imaging methods and software will be distributed to any interested researcher in order to broadly disseminate this technique within the cellular mechanobiology and tissue engineering communities. In addition, graduate students and undergraduate students will be trained in a highly multidisciplinary environment and will mentor high school students for a six-week research experience. The biomechanical imaging computational platform maps intracellular stress distribution through simultaneous measurements of (1) traction forces that are transmitted by cells to the substrate and (2) intracellular displacements generated by externally applied stretch. In this project, the researchers will first improve the ability of the biomechanical imaging technique by using mitochondria as fiduciary markers in order to obtain more accurate maps of intracellular stress. The improved technique will then be used to address two fundamental questions. First, the impact of external stretch on tensional homeostasis of multicellular clusters will be investigated. This will be done using bovine aortic endothelial cells and primary human umbilical vein endothelial cells. Second, the system will be used to unravel the relevance of intercellular stress transmission on tensional homeostasis. This will include the investigation of the role of cell-cell adherens junctions and the impact of substrate stiffness on both cell-cell vs cell-matrix force transmission. 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.