What is surprising is that cells try to do this even when they are being swept away from the region in the flow of other cells. They pull in one direction even as they move in another.
When studying complex organisms like ourselves—ones that grow by developing bones, sprouting blood vessels, and healing wounds—it is hard not to wonder how we manage to organize the molecular building blocks in our bodies. Never before have we known, however, how miraculous their manner of getting around really is. A recent study has revealed surprising patterns in the collective movement of cells that not only provide scientists with a fascinating new set of questions to ponder, but also promise greater insights into regenerative medicine and the treatment of diseases.
The team of researchers at the Harvard School of Public Health (HSPH) and the Institute for Bioengineering of Catalonia (IBEC) that made this unexpected discovery had originally set out to explore the mechanics—the relationship between forces and motions—of collective cellular motion. “We were thinking about this like weathermen,” says Jeffrey Fredberg, professor of bioengineering and physiology in the HSPH Department of Environmental Health and one of the primary authors. “In a weather forecast, the weatherman shows a pressure diagram which displays the forces in the atmosphere, and from this he predicts the velocities of moving gases and the consequent weather conditions. Similarly, we wanted to see if we could predict the motions of cell clusters, now that we could measure the forces acting on them.”
To study these forces, the team developed a technique called “monolayer stress microscopy”, in which cells are put on a gel containing fluorescent particles whose positions can be measured. The deformations of the gel in response to cell movements, as reflected in the motion of the fluorescent particles, provide information about the forces exerted on the gel by the cells, which in turn can be used to compute the forces among the cells. “It’s like in a tug of war, where children in a playground pull on a rope,” Fredberg explains. “The tractions of the gel are like the forces of their feet on the ground, and once you know those forces, you can figure out the tension in the rope. So that shows the intercellular stresses.” While the engineers and physicists of the group devised and executed this technique, the cellular biologists and physiologists designed and evaluated cellular models and looked for the right questions to ask.
After setting up a system with an advancing sheet of cells moving across a cell culture, the researchers put in its path a region to which the cells could not adhere. They did this in order to set up systematic gradients of both stresses and velocities around the obstructions and find the relationship between these parameters.
Instead, the investigators stumbled upon an unexpected behaviour: the cells were pulled towards the region not only when they were approaching it, but also when they were swarming around it and, more mysteriously still, when they were finally flowing past it. It was evident from this that the cells were programmed to fill empty spaces like the obstruction. This programming certainly makes sense, considering the need to close wounds and compensate for losses of cellular systems; what is surprising is that cells try to do this even when they are being swept away from the region with the flow of other cells. In this situation, they pull in one direction even as they move in another.
On first observing this pattern in MDCK cells, a cell type used as a standard model for epithelial cells, which separate the outside of the body from the inside, the team tried to find out if the property was a general one, and tested various types of epithelial and endothelial cells (Endothelial cells are found between the tissues and blood.). In each case, they discovered the same behaviour, which has been named “kenotaxis,” from the Latin words “keno” meaning “vacuum”, and “taxis” meaning “arrangement.”
The foremost question posed by the study, which was published in Nature Materials this June, concerns how cells can so counter-intuitively pull in a direction perpendicular or even opposite to the one in which they are moving. Clearly, there is no simple relationship between the forces and motions. An equally interesting puzzle lies in the fact that this behaviour is observed only in the cellular collective, where cells communicate mechanically, and never in individual cells.
“We also need to find out how this mechanism gets disrupted in various diseases or cancer, and how it can be amplified to accelerate wound healing,” Fredberg says. With the awareness of kenotaxis, scientists can create enhanced model systems involving cell behaviours never before suspected to exist. The lab is presently studying models of cancer and asthma, as well as lung and vessel injuries, where scientists can measure the motions of cells in response to various drugs. “If we understand why cancer cells move the way they do, we might be able to do something about it.”
The implications for regenerative medicine and tissue engineering remain to be fully explored, but the prospects are exciting. For example, the cells and stem cells that are required to invade the extracellular matrix in the body face geometrical obstacles similar to the simplified system in this experiment. Our ability to better understand their movement when faced with such obstructions could help make this process faster, more effective, or more conducive to tissue repair and regeneration.
Individual cells have formed the predominant focus of modern biology thus far; many interesting questions about the cellular collective, and about the relationship between the individual and the collective, now await exploration.Shreya Vardhan is a Brevia staff writer. She can be reached at firstname.lastname@example.org.