Study sheds new light on the molecular mechanisms underlying the development of chronic wounds

A study conducted by NYU School of Medicine researchers, in collaboration with the Wound Healing Program at Columbia University, sheds new light on the molecular mechanisms underlying the development of chronic wounds.

The findings may help clinicians predict which wounds are likely to become chronic - a key bit of information, since the sooner treatment is started, the better the outcome. The research also raises the hope for new treatments for chronic wounds by identifying possible targets for intervention.

Chronic wounds, which include bedsores, are a common and potentially life-threatening problem, typically occurring in people with diabetes or poor circulation, the elderly, and anyone who is bedridden or wheelchair-bound. Bedsores - also known as pressure sores or pressure ulcers - have been estimated to affect about five to ten percent of hospital patients, 13 percent of nursing home residents, and up to 39 percent of spinal cord injury patients in the United States. Chronic wounds can lead to widespread infections and limb amputations, says Marjana Tomic-Canic, Ph.D., Associate Professor of Dermatology and Microbiology at NYU School of Medicine, the study's lead author.

Studying tissue taken from chronic wounds in humans, the researchers discovered that skin cells get stuck in the middle of the normal healing process and cannot migrate to the wound site. The stalling of the healing process, the researchers discovered, is caused by overabundance of a molecule called c-myc (a product of the ubiquitous myc gene, which has been implicated in many human cancers). This molecule is known to suppress cell migration and to cause the skin to thicken, obstructing reparative cells from reaching the edge of the wound.

The cause of c-myc overproduction was then traced one step up the molecular pathway to beta-catenin, a critical regulator of cell behavior. According to the researchers, beta-catenin activates the production of c-myc as well as other pathways that affect the migration, growth, and regulation of skin cells.

This is the first study to investigate the roles of c-myc and beta-catenin in impairment of wound healing in humans. It is published in the July 1 issue of the American Journal of Pathology.

In normal skin, cells are tightly stuck together in order to create a barrier between the body and the outside world, keeping water in and infections out. But when a wound occurs, skin cells from lower layers loosen from their neighbors and start migrating to the wound site and dividing rapidly. Dr. Tomic-Canic and her colleagues found that in skin with chronic wounds, the cells multiply at a higher rate than usual, yet they are unable to migrate into the wound to close it. Instead, they form thickened layers around the edge, much like a callus or a corn.

Something else also goes awry in chronic wounds, according to the study. As skin cells move upwards, they normally lose their nuclei and form sturdy layers of cross-linked proteins, creating a protective layer over the wound. But in chronic wounds, the researchers found, skin cells are unable to progress to this stage of differentiation, and their nuclei remain present.

"The biology seems to be stuck in the middle of these two processes, and can't seem to complete either of them," says Dr. Tomic-Canic.

In the next step of their research, team will try to figure out what causes beta-catenin to accumulate in chronic wounds. In the meantime, they say, the molecules they have identified may make the treatment of chronic wounds more effective.

Doctors have few effective therapies for treating chronic wounds. Usually, the non-healing edge of the wound is surgically removed in order to get rid of the bad tissue. However, it can be difficult to determine how much tissue should be removed. Then, dressings, which may contain growth factors or living cells that skin cells require for healing, are placed over the wound.

If skins cells could be tested for high levels of molecules such as c-myc, says Dr. Tomic-Canic, physicians would be able to tell which cells were already stuck in the non-healing state. Surgeons could then remove this unresponsive tissue and know exactly where the healthy tissue starts. "The skin cells within the edge of the wound that do not have these pathogenic markers or have very little are the million-dollar cells, which you really want to target in therapy," says Dr. Tomic-Canic.

The findings may also be useful in clinical trials of new therapies for chronic wounds, to make sure that the treatments are targeting the right types of cells. In the future, molecules such as c-myc and beta-catenin could be the focus of medications, cutting the chain of wound development before it advances.

The other authors of the new study are Olivera Stojadinovic, Constantinos Vouthounis, Brian Lee, Ankit Merchant, and Robert D.Galliano from NYU; Harold Brem from Columbia University; John Fallon from Mount Sinai School of Medicine; and Michael Stallcup from the University of Southern California.