Mathematical Modeling and Computational Analysis of Cell Movement

University Of Minnesota-Twin Cities, Minneapolis MN

Investigators

Abstract

Cell locomotion plays an essential role during embryonic development, angiogenesis, tissue regeneration, the immune response, and wound healing in multicellular organisms, and has a deleterious effect in cancer metastasis. Movement is a complex process that involves the spatial and temporal control and integration of a number of sub-processes, including the transduction of chemical or mechanical signals from the environment, intra-cellular 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' or `gliding', involves the extension of finger-like protrusions and/or broad, flat protrusions, whose protrusion is driven by actin polymerization at the leading edge. The amoeboid mode is less reliant on strong adhesion, and cells are more rounded and employ shape changes to move -- in effect 'jostling through the crowd' or `swimming'. Cells of the immune system use this mode for movement through tissues when adhesion molecules have been knocked out. 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 their mode of movement accordingly. Thus pure crawling and pure swimming are the extremes on a continuum of locomotion strategies, but many cells can sense their environment to determine the most efficient strategy in a given environment. The long-term objective in this research is to understand how cells sense the mechanical properties of their environment and transduce the information into intracellular biochemical and mechanical changes that determine their pattern of movement. Recent experimental work has discovered that numerous cell types use strong intracellular material flows near the cell wall, which, when disrupted, disrupts cell movement. However, there is as yet little understanding of how this flow translates into cell movement, and our first objective is to continue development and analysis of a mathematical model that facilitates in silico experiments to understand how the processes involved interact to produce motion. Another objective is to understand the cytoskeletal changes needed to produce motion using blebs, which are 'blister-like' protrusions of the membrane, and how the choice between blebs and other modes is arbitrated in complex environments. In particular, the role of membrane tension and the nature of cell confinement in determining how and where on the membrane blebs are initiated, and whether blebs or protrusions are used, are not understood. A third objective concerns movement of cells under various forms of confinement. It is known that imposed mechanical stress can induce movement in otherwise quiescent cells, but how mechanical stimuli induce motion is not understood. A detailed model such as the PI shall develop will provide experimentally-testable predictions that can be used to guide new experiments that advance our understanding of cell movement. 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.