Mathematical modeling and Computational Analysis of Cell Tissue Movement

Cell locomotion plays an essential role during embryonic development, angiogenesis, tissue regeneration, the immune response, and wound healing in multicellular organisms. The major problems to be addressed in this project are (i) movement by shape changes, (ii) modeling of the intracellular mechanics, and (iii) integration of signaling, actin dynamics and mechanics in an integrated computational model of cell movement. Heretofore mathematical modeling has primarily focused on the mesenchymal mode, but the investigators first address the other end of the continuum. The overall objective is to produce a unified description for locomotion in a three-dimensional extracellular matrix that integrates signaling and mechanics. Movement by shape changes has not been studied in the context proposed, but it has recently been shown to be important in the movement of a number of cell types, and understanding the factors that affect the speed and efficiency of such movement is a challenging problem. This project develops mathematical models that can be used to study and quantify the importance of various factors, such as properties of the surrounding medium, that affect the efficiency of movement. The third component continues previous work by the principal investigator on signaling and will integrate a model of the control networks with the mechanical components that comprise the first topics. This will lead to the first model that incorporates both signaling and mechanics, and will result in a computational tool that should be very useful to the broader community.

Cell movement is a very complex process that involves the spatial and temporal control and integration of a number of subprocesses, including the transduction of chemical or mechanical signals from the environment, intracellular biochemical responses, and translation of the intra- and extracellular signals into a mechanical response. While many single-celled organisms use flagella or cilia to swim, there are two basic modes of movement used by eukaryotic cells that lack such structures--mesenchymal and amoeboid. The former, which can be characterized as ?crawling? in fibroblasts or ?gliding? in keratocytes, involves the extension of finger-like pseudopodia and/or broad flat lamellipodia, whose protrusion is driven by actin polymerization at the leading edge. In the amoeboid mode, which does not rely on strong adhesion, cells are more rounded and employ shape changes to move--in effect 'jostling through the crowd' or 'swimming'. However, recent experiments have shown that numerous cell types display enormous plasticity in locomotion, in that they sense the mechanical properties of their environment and adjust the balance between the modes. Thus pure crawling and pure swimming are the extremes on a continuum of locomotion strategies, but many cells can sense their environment and use the most efficient strategy in a given context. This project uses innovative mathematical approaches to better understand the dynamics of cell locomotion, combining novel models with experimental data. Additionally, the research team includes postdoctoral researchers and graduate students, with the project providing an opportunity to work in an inherently interdisciplinary field.