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.jpg "Non-polarized cell six hours after seeding onto a compliant fibronectin-coated substrate. Yellow shows paxillin, a protein associated with focal adhesions")
Adhesion, as they say, is a sticky business, especially for a cell. The adhesion complexes linking a cell’s outer surface to neighboring cells and connective tissues consist of hundreds of different proteins. These not only hold the cell in place but also sense the properties of the cell’s surroundings and relay that information to the inside of the cell. So crucial is the adhesion-mediated process, according to new Institute research, that even cells that actively migrate must first “stick around” in order to get into traveling shape.
Profs. Benjamin Geiger and Alexander Bershadsky of the Molecular Cell Biology Department are interested in the ways that cells sense and respond to the physical properties of their environment. Blood pressure, muscle tension, and tissue stiffness and tension are all features and forces that act on cells, affecting their behavior and fate. Included in these is the capacity of cells to generate contractile forces of their own. When a cell contacts a surface, for example, it first attaches weakly and then contracts so as to probe the surface with the force of its pull. If this test indicates that the surface is adhesive and displays the proper mechanical properties (i.e., rigidity), it adheres, extending its adhesion complexes into so-called focal adhesions and spreading itself out. To begin revealing the intricate relationship between an adhering cell and its substrate, Geiger and Bershadsky, together with postdoctoral fellows Drs. Masha Prager-Khoutorsky and Alexandra Lichtenstein, designed and constructed an experimental system in which cells were placed on adhesive polymer surfaces that had similar chemical properties and differed only in their stiffness. Their findings were published in Nature Cell Biology.
They found that the differences in the cells’ behavior were immediately apparent: The cells on the softer surfaces spread out equally in all directions, forming tiny, circular “fried egg” configurations, whereas those on the stiffer surface became elongated. Elongation gives cells polarity – a “head” and “tail.” This pear shape enables the cells to take off and migrate, an essential property for embryonic development, wound healing, and tissue growth and repair. A closer look revealed differences in the focal adhesions. The round cells on the softer surface had adhesions that were small and evenly distributed all around or throughout. By contrast, on the rigid surfaces, the focal adhesions were large, and these tended to align with the future head and tail regions of the cell even before elongation was observed. In other words, whether a cell is sleek and travel-worthy or comfortably round is directly connected to the rigidity of the substrate it adheres to. Focal adhesions, among other things, function as the rigidity sensors.
To understand the focal adhesion process on the molecular level, the researchers, using gene silencing technology, systematically depleted various genes that encode specific signaling cellular proteins – some 80 different genes in all – and they tested how each modified cell responded to its surface. The Institute’s Prof. Zvi Kam provided essential help with microscopy, automatic image analysis and quantification, and Dr. Ramaswamy Krishnan of Harvard University assisted with a method for measuring the forces applied by the cells to the underlying substrate.
Some of the cells with silenced genes lost their ability to polarize or to form different sizes of focal adhesions in response to the substrate rigidity; in others, the cells’ grip on the surface or the detection of force was affected. The researchers concluded that cell polarization is a highly complex process – one that is driven by mechanical force and mediated by focal adhesions. Regulation of this process occurs in multiple stages, affecting the generation of cellular forces as well as directing the response to force. “We were surprised at how many regulatory factors are involved,” says Bershadsky. Geiger: “We have revealed a strong tie between the development of focal adhesions, the generation of force and cell migration, and have identified some of the critical regulators of this process.”
Their findings may have relevance for many areas of biology and basic biomedical research. For instance, the scientists believe the insights they have gained may be relevant to processes affecting the cells lining the blood vessels. These cells are often exposed to turbulent blood flow or regular pressure changes, which can contribute to arterial plaque formation and aberrant collateral blood vessel development. Understanding the process may help to identify potential therapeutic targets for such disorders.
Prof. Alexander Bershadsky's research is supported by the Kahn Family Research Center for Systems Biology of the Human Cell. Prof. Bershadsky is the incumbent of the Joseph Moss Professorial Chair of Biomedical Research.
Prof. Benjamin Geiger's research is supported by the Leona M. and Harry B. Helmsley Charitable Trust; and IIMI, Inc. Prof Geiger is the incumbent of the Professor Erwin Neter Professorial Chair of Cell and Tumor Biology.
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