PHILADELPHIA -- Researchers at the University of Pennsylvania and Cornell University have pinpointed a fundamental mechanism that controls how cells coursing through our blood "know" when to exit the bloodstream and go to work in the body's tissues. The secret, they report in the Sept. 26 issue of the Proceedings of the National Academy of Science, are so-called "Goldilocks molecules" that bind blood cells to the walls of veins and arteries neither too strongly nor too weakly, but with just the right level of adhesion.
Lead author Daniel A. Hammer, Ph.D., professor of bioengineering and chemical engineering at Penn, likens this process, known as cell trafficking, to the use of ZIP codes to direct mail to communities nationwide. The presence of one of a handful of key molecules on the surface of a cell, he says, guides the cell just as surely as a five-digit number on an envelope ensures that a piece of mail reaches a particular city.
"Trafficking of blood-borne cells into tissues is crucial to the proper function of the immune response," says Dr. Hammer, a member of Penn's Institute for Medicine and Engineering. "Inflammation, lymphocyte function, and bone marrow replenishment after transplantation all depend upon it."
While cell trafficking is ordinarily a beneficial and necessary process, researchers also suspect that it's responsible for the metastasis of cancerous cells that move with great precision from the site of an initial tumor to colonize secondary areas. Virtually all primary tumor locations are strongly associated with secondary locations where cancer is most likely to reassert itself later on, Dr. Hammer says. For instance, people who develop skin cancer often subsequently develop lung cancer -- suggesting that melanoma cells may be programmed to direct themselves to the lungs.
Cells exit the bloodstream millions of times per second, binding fleetingly to vessel walls before slipping through them into the surrounding tissues. The process begins with what's called "rolling adhesion": blood cells skipping along the walls of veins and arteries pause occasionally when molecules on their surfaces form transient bonds with vessel-bound receptors. But only if a bond forms between just the right molecules will the cell be ushered out of the bloodstream.
Of the more than 100 adhesion molecules known to exist on the surfaces of blood cells, only a half dozen with very specific chemical and mechanical properties play a role in directing the cells to their rightful targets. As Dr. Hammer and his colleagues report in PNAS, the factors that differentiate between run-of-the-mill adhesion molecules and those involved in cell trafficking are the strength and duration of these ephemeral adhesions.
"I call these 'Goldilocks molecules,'" Dr. Hammer says. "For cells to exit the bloodstream, you need just the right adhesion. It can't be too tight, or the cells will bind to the vessel wall and never let go. It can't be too weak, or the blood cell will just pass on by."
In their research, Dr. Hammer and his colleagues used a computational method to mimic adhesion between a blood-borne cell (in their case, a simulated leukocyte) and a surface like that of a blood vessel wall. By examining the effect of fluid forces on adhesion, they determined the relationship between molecular strength and the adhesion between blood cells and blood vessel walls; the stronger a bond, the more forceful the flow of liquid required to sever it. Dr. Hammer says the successful use of this method in his group's study could make it a new model for researchers interested in studying the chemical and mechanical properties of bonds, and may ultimately be used to design bonds that have tailored mechanical properties.
The findings may also be useful in the Human Genome Project, as they help explain the relationship between the structure and function of molecules, ultimately explaining how molecules work.
Dr. Hammer was joined in the research by David F.J. Tees, Ph.D., a postdoctoral researcher in bioengineering and chemical engineering at Penn, and Kai-Chien Chang of Cornell's Department of Chemical Engineering. Their work was funded by the National Institutes of Health.
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