Forcing Organization in Multicellular Assemblies

Many biological functions are regulated by the coordination of mechanical forces and biological signals that are transmitted across multiple length scales in tissues. Proteins on cells sense and respond to mechanical forces, by activating biochemical signals. These signals can alter the mechanical properties of entire cells, interactions between cells, and even the organization of clusters of cells into complex tissues.

However, the current understanding of how mechanical forces regulate human physiology is limited. This award supports basic research that will uncover mechanisms by which forces at the protein level regulate cell mechanics and ultimately direct tissue scale behaviors. This research has significant implications for understanding how tissues form, how embryos develop, and how diseases progress.

The knowledge gained from these studies could lead to advances in tissue engineering and medicine that would enhance national health and welfare. This program will support the education and training of students from underrepresented groups across multiple disciplines, to broaden their participation in Science, Technology, Engineering and Mathematics.

Intercellular adhesion proteins, cadherins, play a major role in directing multicellular organization in vivo and in vitro, but the mechanical properties of individual cells also play a major role and may even override cadherin adhesion specificity. This program directly addresses a long-standing conundrum concerning the importance of cadherin identity (biochemistry) and cell mechanics in multicellular organization.

The research is interdisciplinary and will leverage molecular biology, bioengineering, materials science, and computation. Cells will be engineered to express cadherin mutants that alter mechanisms of force transduction. Clusters of these cells will be cultured in micropatterned matrices with tunable mechanical properties.

Complementary mechanical, imaging, and computational approaches will be used to quantify the impact of altered force transduction mechanisms on cell mechanics, intercellular adhesion, and multicellular organization. The planned studies are based on substantial preliminary data and published work by the co-investigators. The findings will establish how critical mechanical switches at cell-to-cell (cadherin) junctions regulate cellular mechanics and morphology, to direct cell organization and invasion in three dimensional, multicellular systems.

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.