Biomedical researchers have suspected for some time that a certain type of protein molecule known as a cadherin plays a role in the way cells convert mechanical signals into chemical activity at the junction where the cells meet. University of Illinois Bioengineering affiliate faculty Deborah Leckband and Ning Wang have shown for the first time that cadherin complexes, which hold cells together in all tissue, do serve as tension tensors that “feel” the mechanical environment of the cell and proportionally modify cell functions.
“Our [work] shows convincingly that cadherins are bona fide mechanosensors,” said Wang, a professor of mechanical science and engineering.
University of Illinois Bioengineering affiliate faculty Deborah Leckband and Ning Wang have shown for the first time that cadherin complexes, which hold cells together in all tissue, do serve as tension tensors that “feel” the mechanical environment of the cell and proportionally modify cell functions.
Their work, conducted in collaboration with researchers at the Hubrecht Institute in the Netherlands, is important because cadherins regulate critical barrier properties of soft tissues such as the vascular endothelium, which lines the inside of blood vessels and the heart. The cadherins essentially control the passage of molecules and liquids across cell layers.
“What our data show is that changes in the mechanical environment of the cell—such as near atherosclerotic plaques or in tumors—will alter the cell-cell junctions, changing the behavior of the cadherins and possibly making them leakier or altering the ability of drugs to cross tissue barriers to treat disease,” said Leckband, the Reid T. Milner Professor of Chemical Sciences.
The researchers findings, which were published in the June 28, 2010, issue of the Journal of Cell Biology, may also have an impact on better understanding cancer metastasis, where diseased cells inside a tumor break their contacts with other cells and migrate to other parts of the body.
“It’s widely known that the rigid environment of a tumor actually promotes metastasis,” Leckband explained. “Our data suggests that forces within a tumor cell will influence how easy or hard it is for the cell-cell junctions to open up and enable cancer cells to escape the tumor.”
Using a technique developed by Wang’s group, the researchers attached micrometer-size magnetic beads coated with recombinant ligands to cell surfaces. After magnetizing the beads, the researchers applied a torque onto the beads and measured the resistance as the inverse of how much the beads rotated. They were able to measure mechanical signals for up to 50 cells per test.
According to Wang, his magnetic twisting cytometry (MTC) is a very useful way to directly determine whether a surface protein such as the cadherin is a mechanosensor or not. Other techniques such as a laser tweezer or an atomic force microscope (AFM) have limitations. For example, the laser tweezer cannot provide a good measurement, said Wang, because it doesn’t generate enough force; the AFM is difficult to set up, has limited frequency range, and can only measure only one cell per test.
Wang originally used the MTC technique in the early 1990s in a ground-breaking experiment that demonstrated that integrins, which are receptors that mediate attachment between a cell and the tissues surrounding it, are mechanosensors.
Although their work was limited to E-cadherins, the results should apply to the other classes of cadherins found in the body. “Our finding could affect cell-cell junctions in all soft tissue,” said Leckband.
In addition, their findings about the cadherin mechanical sensing could help researchers understand how different tissues ultimately grow into organ systems during embryonic development. “During early embryogenesis, cadherin-mediated cell to cell adhesion is force dependent and this force may dictate tissue patterning and the organogenesis of a human being,” said Wang.
Now that they’ve established how critically important cadherins are in biology, the Illinois researchers plan to examine how mechanical forces affect the shape and strength of cell-cell contacts.
“We also have funding to look at signaling pathways, which is where potential drug targeting comes in,” Leckband explained. “If we could potentially identify key signaling pathways that are affected by force, then we could identify molecular components that could be targeted by specific drugs.”