Miller Researchers Discover Novel Mechanism Orchestrating Wound Closure

A new discovery by researchers at the University of Miami Miller School of Medicine could provide the answer to a long-standing mystery: why do some people have skin wounds that heal relatively quickly while others develop serious wounds that become resistant to closure over time?

The culprit might be a membrane protein called caveolin-1, which inhibits re-epithelization (the migration of new skin across a wound) when present in high amounts, Marjana Tomic-Canic, Ph.D. and colleagues report in a new study in the journal Molecular Therapy.

One surprising finding was “such remarkable absence of caveolin-1 in cells that are participating in epithelial migration,” said Dr. Tomic-Canic, senior study author and professor, vice chair of research and William H. Eaglstein Chair in Wound Healing in the Dr Phillip Frost Department of Dermatology and Cutaneous Surgery at the Miller School.

Another unexpected result was the common finding among different types of chronic wounds, such as diabetic foot ulcers and venous leg ulcers, “that makes it even more attractive for therapeutic use,” she added.

Not only did the research team identify the harmful role of caveolin-1, but they also proposed therapeutic solutions. They demonstrated, for example, that suppressing caveolin-1 either with drug treatment or through gene therapy accelerated wound closure.

Their findings carry implications for the large number of people who live with chronic wounds that remain very challenging to treat, leaving them open to risk of serious infections and other adverse effects.

“Chronic wounds represent a major clinical problem that affects millions of people worldwide. Despite the urgent medical need, no new therapies that meet efficacy threshold in randomized clinical trials have emerged in past two decades,” Dr. Tomic-Canic said.

“This research not only discovered a molecular pathway that is potential target for new therapies, but also tested pharmacologic inhibitor providing a clear path for further clinical applications,” added Ivan Jozic, Ph.D., a research assistant professor of dermatology who was lead author of the study.

Dr. Tomic-Canic, Dr. Jozic and their colleagues found that caveolin-1 inhibits wound closures in multiple pre-clinical experiments. They further confirmed the findings by taking biopsies from the edges of chronic non-healing wounds; this work demonstrated the membrane protein was overexpressed. At the same time, healing wounds featured low levels of caveolin-1.

Interestingly, inhibiting caveolin-1 through a pharmacologic or gene editing method might offer hope to people with chronic non-healing wounds. The investigators showed that treatment with methyl-?-cyclodextrin (M?CD) can suppress activity of the membrane protein. Alternatively, a genetic “knockdown” of caveolin-1 also promoted accelerated wound healing.

“We discovered that caveolin-1 is one of the molecules that is induced in patients with chronic non-healing wounds, such as diabetic foot or venous leg ulcers. Conversely, we found it suppressed in healing wounds,” said Dr. Jozic, who presented this study at the Innovations in Wound Healing 2019 annual meeting on December 5.

The caveolin-1 breakthrough would not have been possible without collaboration.

“This is an example of team science at its best,” Dr. Tomic-Canic said. “Only a team effort from bench scientists, the clinical researchers at our wound healing research clinic, and devoted patients could result in such important discoveries, which simultaneously teach us why wounds do not heal and, at the same time, point toward new treatment strategies.”

Going forward, the researchers plan to dive deeper into the mechanisms driving the role of caveolin-1 in wound healing, and more generally, in the skin. A second aim is to continue developing an effective topical treatment based on their research.

Multiple grants from the National Institutes of Health, as well as a PhRMA Foundation Research Starter Grant and a Medline Wound Healing Foundation grant supported this study.

Tags: Caveolin-1, dermatology, Ivan Jozic, Marjana Tomic-Canic, wound closure, wound healing