UI study discovers cells segregate molecules to control signaling

The human body has barriers such as skin and the lining of airways and gut that protect and separate us from the outside world. If these barriers are breached, our survival is threatened. Therefore it is critical that the cells that form these barriers have mechanisms that can instantly repair any injury.

University of Iowa researchers have discovered a surprisingly simple but effective repair system in airway barrier cells. The UI study shows that by placing a messenger molecule on one side of the barrier and a receiver molecule on the other side, these cells have in place a repair mechanism that is poised to leap into action whenever the barrier is breached. The study findings are published in the March 20 issue of Nature.

One of the researchers, Joseph Zabner, M.D., associate professor of internal medicine, likened the repair mechanism to a situation where a broken fence allows a neighbor’s dog to come in and bother a farmer’s chickens. The dog causes the chickens to squawk, which signals the farmer to go and fix the fence. In the same way, breaks in the cell barrier allow the messenger molecule to get to the receiver, which then sends a signal to the cell to repair the broken barrier.

“If everything is healthy, the message never gets to its receptor because the barrier keeps them apart,” said Paola Vermeer, Ph.D., UI assistant research scientist and the lead author of the study. “The instant that barrier is broken, the message can get to its receptor and that receptor sends the signal to start the repair process.”

The findings explain how healthy barrier cells can rapidly repair injuries. The results may also have important implications for disease processes.

If a disease weakens the barrier in such a way that allows the message to get to its receptor when it shouldn’t, then the repair mechanism may be turned on inappropriately. Such continuous signaling could lead to cellular abnormalities and may play a role in diseases where barriers are important.

“’If this mechanism is disrupted in disease, then these findings might suggest targets for therapeutic intervention,” added Michael Welsh, M.D., the Roy J. Carver Biomedical Research Chair in Internal Medicine and Physiology and Biophysics, UI Professor, and Howard Hughes Medical Institute Investigator. “It might be possible to interfere with the message or its receptor to break the line of communication.”

The UI team studied airway epithelial cells, which form the barrier lining the bronchial passages. In this system the researchers looked at a message molecule called heregulin, which is a growth factor, and receiver molecules known as erbB receptors. Heregulin was present on the upper, mucosal surface of the epithelial cells and in the liquid overlying the airway surface. In contrast, the erbB receptors were segregated to the other side of the epithelium where they were located exclusively on the bottom or basolateral surface of the cells.

The UI study found that with the barrier intact, there was no communication between heregulin and its erbB receptor. However, when the researchers damaged the epithelial cell barrier, heregulin immediately gained access to its receptor. This communication triggered cell growth and differentiation leading to rapid repair of the injury.

Certain airway diseases such as asthma, cystic fibrosis and smoking-associated bronchitis are known to impair the airway barrier. The UI study suggests that under these disease conditions heregulin or other messenger molecules might not be well segregated from their receptors, and the receptors might be activated abnormally.

“We asked what would happen in our cell cultures if the erbB receptors were permanently turned on,” Vermeer said. “After 10 days the cells were overgrown and showed abnormal structure.”

The airways of individuals with these airway diseases also undergo many cellular changes, including a thickening of the airway lining caused by excessive cell growth.

Welsh commented that the results of this study might also be relevant to many other biological systems where a barrier separates a message molecule from its receptor.

“When cancer cells grow, they often lose their barrier function,” Welsh said. “We speculate that might mean that signaling molecules could gain access to their receptors, and this might stimulate cell growth.”

The separation mechanism may also be important in controlling developmental processes because immature cells do not possess the barriers found in mature cells.

In addition to Vermeer, Zabner and Welsh, the UI researchers involved in the study included Lisa Einwalter, Thomas Moninger, and Tatiana Rokhlina. Jeffrey Kern, M.D., division chief of pulmonary and critical care medicine at University Hospitals of Cleveland, also was part of the team.

The research was funded in part by grants from the National Institutes of Health and the Cystic Fibrosis Foundation.

University of Iowa Health Care describes the partnership between the UI Roy J. and Lucille A. Carver College of Medicine and UI Hospitals and Clinics and the patient care, medical education and research programs and services they provide. Visit UI Health Care online at http://www.uihealthcare.com.