The Mechanics of Cell Migration

The migration of mammalian cells is necessary for such processes as wound healing, embryonic development and cancer metastasis.  Thus it is important to understand how cells orchestrate their movement.  Migration involves a series of highly coordinated events including extension and adhesion of the leading edge, contraction of the cell body, and de-adhesion and retraction of the trailing edge.  These events are interlaced with mechanical and chemical interactions that are both intercellular and extracellular.  My research is focused on understanding the role of mechanical forces in cell migration.

As a cell migrates, just as when we walk, internal mechanical forces are transferred externally to produce forward movement. These forces on the substrate are referred to as traction forces and can be measured biophysically. When the force machinery is experimentally manipulated we can begin to understand how these forces are produced. Key structures in the production of this force include the acto-myosin cytoskeleton and focal adhesion, both highly dynamic multi-protein structures. We are currently studying the formation and disassembly of these structures and the affect on traction force.

The mechanical and topographical properties of the extracellular environment can also influence cellular behavior. For example, a cell can sense the rigidity of its substrate and respond by either migrating towards or away from the substrate. We have also found that a macrophage can sense the mechanical composition of a phagocytic target and preferentially engulf more rigid particles. Currently the mechanism of this mechanosensing phenomenon is unknown.

Additionally, cells are capable of sensing the topography of their environment and display a variety of morphological and biochemical phenotypes in response to changes. One dramatic example is the differences observed between cells cultured in two- versus three- dimensional cultures. We have recently demonstrated that this difference can be manipulated by engagement of dorsal extracellular matrix receptors and requires appropriate mechanical input. Mechanistically we have determined that both calcium and the protease calpain are necessary for this response. In future studies we will further define these mechanisms and explore their significance to cancer formation and metastasis.

 

Figure1: Traction forces measured beneath a fish fin fibroblast expressing a GFP-labeled focal adhesion protein zyxin. Vector plots indicate magnitude and direction, and color plots indicate magnitude with red being the strongest forces and blue the weakest.

 

Figure 2: Gently sandwiching a mouse fibroblast between two fibronectin-coated substrates initially engages dorsal receptors above the nucleus.

Figure 3: Fibroblasts respond to dorsal receptor engagement by elongatinginto spindle and stellate shapes typically observed in histological sections.

 

 

Visualization of Traction Stress


Visualization of Traction Stress

The distribution of traction stress vectors can be visualized as a map of arrows, as standard practice of studying vectorial fields. However, an equally useful approach is to render the magnitude of traction stress vectors as color images, with "hot" color corresponding to strong forces and "cool" color corresponding to weak forces (right-side of the video). Vector plots have the advantage of displaying both the directional and magnitude information. Color rendering, on the other hand, proves to be superior for visualizing dynamics in time-lapse studies

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