BIOPHYSICS

Shape-shifting of Cells Gives Body Stretch

Change from Solid to Liquid and Back Underlies Tissue Flexibility

How is the ketchup that stubbornly hugs a glass bottle but then gushes in one burst similar to the cells of your body? According to research by Jeffrey Fredberg, the same physical property that makes topping a hamburger so frustrating may be what allows cells to change shape in response to physical forces. For the past several years, Fredberg’s lab has been following a surprising discovery: that cells behave like glass, or more specifically, like “soft glassy materials,” a category that includes such mundane materials as ketchup, toothpaste, shaving foam, clay, and mayonnaise. A paper in the May 31 Nature from the lab offers evidence that cells have the ability to shift from a solid to a liquid form the way these materials do, an ability that might underlie cells’ astounding physical flexibility.

Graham Ramsay

Jeffrey Fredberg (left) and Xavier Trepat found that when cells feel a tug, they loosen up, a strategy that might help them withstand changing physical conditions in the body.

Go with the Flow
Fredberg, HSPH professor of bioengineering and physiology, began this research when studying the problem of why the airways of people with asthma are not able to expand with a deep breath during an asthmatic attack. He and his lab members began subjecting individual muscle cells to mechanical forces to understand how cells react to the stretching forces of breathing. Surprisingly, the data they collected indicated that cells behave much like soft glassy materials (see Research Briefs, Focus, Nov. 9, 2001). These materials are not rigid like glass but act as solids until enough force causes them to fluidize.

Yet even though the data fit a certain type of material, Fredberg wanted to see whether the analogy would hold up under closer scrutiny. In this latest study, Fredberg’s team, led by research fellow Xavier Trepat, subjected individual smooth muscle cells to brief stretches, similar to the kind of force that cells undergo in airways. The team attached tiny magnetic beads to the cell surface that slightly deform the cell when they align with a magnetic field. The researchers calculated how much the beads were displaced—very little movement signaled that the cell was stiff, while lots of movement indicated it was floppy.

The researchers discovered that in response to a quick tug, cells do not stiffen to maintain their shape. “After stretching the cells, we found that the beads move more easily, meaning the cells are softer and more fluidlike than solidlike,” Trepat said. After fluidizing rapidly, cells gradually recover and return to a solid form, a behavior that is also found in soft glassy materials.

The researchers then treated cells with different drugs, each of which interfered with cell shape or behavior. They found that cells still fluidized even if they lacked important structural proteins, like actin and myosin, or if they were depleted of energy in the form of ATP. The same response was seen in different cell types, including cells from the lung, kidney epithelium, and bronchial passage.

“This is not attributable to any one component,” Fredberg said. “This is a nonspecific effect.” He added that the universality of the response is very different from typical behaviors studied in a cell, which are usually dependent on one or more specific interactions.

The team then looked at the cell responses on a molecular scale. Beads attached to the cells normally make tiny hopping motions, which are thought to be an indicator of the subtle molecular rearrangements of the cytoskeleton that happen within the cell at all times. By measuring these spontaneous movements, the researchers found that the contents of the cell became much more dynamic when cells were stretched briefly and then released, signaling that the cell was reorganizing.

Universal Switch
Fredberg believes that the ability to become soft and fluid might be the key to understanding what goes wrong during an asthma attack. This behavior might also become important in other parts of the body under physical stress, like the cells in the circulatory system and gut, as well as in fetal development, infection, and cancer. Cells must hold their shape under a variety of forces and maintain the structure of tissues, but under certain circumstances, they also need to contract, divide, crawl, and change shape, which Fredberg believes must require switching physical states.

Trepat said that the next question to address is how this broad, nonspecific behavior of cells affects the detailed signaling pathways that biologists traditionally study. “What are the functional implications of this behavior in the cell?” he asked. “This earthquake happens inside the cell. We want to see how resulting fluidization modulates these pathways and to what extent these pathways contribute to the universality of this response.”

According to David Weitz, the Mallinckrodt professor of physics and applied physics at Harvard University, Fredberg is opening up new ways of thinking about biological materials. “To me, what’s very interesting is that Jeff is applying concepts of materials science to cells and showing that many of the ways of thinking about materials also apply to a cell. In the end, a cell is a material.” And though it should not be surprising that cells share physical properties with inert materials, Weitz said, biologists are not typically trained in the concepts or experimental methods necessary to study them in that way. Fredberg’s work is showing that “there is tremendous value in looking at these biological systems, cells, and taking a materials science perspective.” In addition, he has had to adapt traditional ways of studying materials to delicate living objects.

Though Fredberg’s thesis has been controversial, it is helping to bring together two disciplines that were once completely separate. Research on soft glassy materials can shed light on the behavior of cells, but as Fredberg points out, information can go the other way, too. It turns out that these substances, which are a hot area of materials science, are incredibly mysterious even though they are found in some of the most everyday places. As Fredberg said, “We still don’t understand the physics of toothpaste.”

—Courtney Humphries

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