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Thrust 3 - Cellular and Multicellular Systems

Large scale assemblies composed of multiple cells are ubiquitous, ranging from tissue to biofilms, and exhibit striking emergent behaviors controlled by cell mechanics and cell-cell interactions are the focus of Thrust 3.

Over the years, it has become increasingly clear that it is not only biochemical factors that are important but that mechanical forces can play a salient role in directing cell behavior and mediate interactions. In this thrust, we therefore focus on the role of mechanics and mechanical interactions in emergent function at various levels – single bacterial cells, artificial constructs of unicellular groups and developing tissue. This thrust, which deals with the cellular level of organization of biological matter synergizes with the biomolecular (Thrust 1) and macromolecular assemblies (Thrust 2) levels of organization and forms a key component of our overall center’s mission of using an interdisciplinary approach combining physical, biological and engineering methods to understand and exploit the functioning of multi-scale assemblies of biological matter. Two specific examples this research thrust will highlight are:

  • Bacterial community motility: This subproject involves understanding the responses of single motile bacteria to mechanical constraints and how unicellular systems can collectively interact to achieve multicellular motility. Specifically a combination of 3D tracking microscopy and a chemical biology/materials approach will be used to (i) quantify the mechanics and response of single swimming bacteria (ii) understand how swarms of unicellular cells with known behavior coordinate to achieve multicellular motility and (iii) identify and formulate physical rules that control directed motion of multicellular aggregates to use as design principles. This will allow for constructing from the bottom-up, multicellular composite ‘organisms’, specifically by coaxing unicellular motile cells to exist as 3-D multicellular constructs

  • Differentiating tissue: This sub-project is a targeted effort to understand, quantify, and direct mechanical signaling in differentiating stem cell populations. Cell fate behaviors are guided by integrated biological, biochemical, and physical (i.e. mechanical) cues, but the fundamental processes involved in such integration remain poorly understood. Here we propose to combine a novel cell system that can fluorescently report cell commitment in real time with a dynamic scaffold system that can generate spatially and temporally engineered forces thus offering a versatile platform for studying the effect of mechanical forces on cell fate.

Specific training under this project will include 3D tracking microscopy, rheometry, light-sheet imaging, particle velocimetry, two-photon absorption, high-speed imaging, microfluidic device fabrication, atomic force microscopy, optical imaging, rapid optical trapping, display applications and surface micromachining, stem cell culture, stem cell differentiation, immunofluorescence imaging, single cell flow cytometery and computer simulation and modeling methodologies including Brownian dynamics and Monte Carlo methods and numerical solutions of differential equations.