Image of skin would trying to heal
Representative image of human skin wound showing neutrophil (teal) recruitment to promote a proper inflammatory response during healing.
Credit Andrew Sawaya, Ph.D., Laboratory of Skin Biology, NIAMS

Unlike acute wounds, such as a paper cut or scraped knee, chronic wounds can take months to heal and leave a person at greater risk for developing infection, chronic pain, and other problems. Slow-healing foot ulcers, a complication of diabetes, are a common type of chronic wound. Diabetic foot ulcers can greatly impact a person’s quality of life and put them at risk for limb amputations or early death. Treating diabetic foot ulcers represents a significant challenge to doctors and costs billions of dollars annually in the U.S.

In a new study published in Nature Communications, researchers identify defects in the wound healing process that might explain why such wounds heal slower or not at all.  The scientists also pinpoint a critical step in the pathway, the series of events contributing to wound repair, that might be a good target for developing new treatments for diabetic foot ulcers.

The collaboration included groups led by two established skin biologists. Maria Morasso, Ph.D., is chief of the Laboratory of Skin Biology at the National Institute of Arthritis and Musculoskeletal and Skin Diseases. She is an expert in skin barrier formation and function and has contributed to our understanding of rapid wound healing. Marjana Tomic-Canic, Ph.D., is a professor of dermatology and director of the Wound Healing and Regenerative Research Program at the University of Miami. She is a leader in chronic, non-healing wound research.

The new paper underscores the power of scientific collaboration. Morasso and Tomic-Canic brought multi-disciplinary teams together under one mission—to heal patients. First, the scientists analyzed human tissue samples to identify the molecular culprits responsible for delayed healing. Then they confirmed their findings using specialized laboratory mice. The long-term goal of the work is to find ways to improve chronic wound healing in humans.

This collaborative research was made possible by an NIH Bench-to-Bedside and Back Program (BtB) Award. The NIH BtB Program was established in 1999 to encourage collaboration between NIH’s intramural researchers and their colleagues at institutions around the country. The goal of the program is to translate basic scientific findings into real-world treatments for patients.

Chronic Wounds Struggle to Heal

Wound healing is a normal process that involves four tightly controlled stages. The second stage, the inflammatory phase, is thought to be the engine that drives the process. During this stage, white blood cells gather at the wound. These cells fight off infection and recruit other immune cells that promote tissue repair.

Chronic wounds heal very slowly because they do not advance through all the phases. Instead, chronic wounds seem to get stuck. They are unable to get past the inflammatory stage. This can lead to additional complications, such as wound infections, or even limb amputations.

Scientists don’t fully understand why chronic wounds halt at this stage, so it has been difficult to design effective treatments. As evidence, current treatment options for diabetic foot ulcers are very limited and no new therapies have been developed in the past 20 years.

The researchers started their investigation of chronic wounds in a body part where wounds heal very quickly—the mouth. Think about the last time you bit your cheek while eating. You probably experienced sharp pain as your teeth pierced the tissue, but the wound healed within a few days.

Previous research from the Morasso group uncovered factors that allow mouth wounds to heal rapidly. This knowledge of rapid wound healing has markedly advanced the understanding of delayed chronic wound healing.

Lack of FOXM1 is Key to Delayed Healing

The scientists sought to uncover what goes wrong in chronic wound healing by studying three different types of healing: injuries in the mouth (fast healing), skin injuries (average healing), and diabetic foot ulcers (slow healing).  Morasso, Tomic-Canic, and their collaborators collected human tissue samples for each of these three types of injury. Then they used a common gene sequencing technique to take a close look at the molecules involved in wound healing. Collectively, these molecules—specific genes and the proteins that control them—are known as a transcriptional network.

This strategy led to some interesting discoveries that could explain why chronic wounds heal slowly.  Right away, the team noticed transcriptional networks that control white blood cell movement and survival were revved up in mouth and skin tissues. Particularly striking was that the tissues were flooded with specialized white blood cells called neutrophils and macrophages, which are essential to wound healing.

A very different picture was revealed in diabetic foot ulcers: transcriptional networks were weakly activated, and neutrophils and macrophages were absent from the tissue.  Diabetic foot ulcers are unable to accumulate these critical white blood cells, which might partially explain why these wounds are slow to heal.

So, what causes white blood cell recruitment to go awry in diabetic foot ulcers? The scientists used computer-based software to scan through transcriptional networks to find a possible key. The analysis pinpointed the FOXM1 protein.  FOXM1 is a regulator that triggers the recruitment of white blood cells.

Sure enough, when the scientists examined levels of FOXM1 in the three types of tissue, they found that FOXM1 was suppressed in diabetic foot ulcers but strongly activated in mouth and skin wounds. If scientists could somehow increase FOXM1 in diabetic foot wounds, they might be a step closer to a treatment for these hard-to-heal wounds.

Although the research seems promising, it was done in isolated human skin tissues, which don’t replicate the complexity of a living organism. To confirm the role of FOXM1 in a living system, the scientists turned their attention to wounded diabetic mice. Diabetic mice are a well-established animal model for studying diabetes.

One group of wounded diabetic mice received a chemical to block FOXM1 activity, mimicking the FOXM1-deficient environment found in diabetic foot ulcers. A second group of wounded diabetic mice did not receive the FOXM1-blocking chemical and served as a control.

If FOXM1 is necessary for proper healing, then blocking its activity should slow the healing process.  Indeed, mice treated with the FOXM1 blocker experienced reduced recruitment of immune cells and slower healing compared to the untreated mice.  These results confirmed that FOXM1 is essential for the healing of wounds, and that, without it, healing is delayed.

Future Directions

Morasso and Tomic-Canic uncovered important clues that explain why chronic wounds are slow to heal.  Their collaborative research on diabetic foot ulcers, a common type of chronic wound, revealed that the absence of FOXM1 led to insufficient recruitment of specialized white blood cells and delayed healing. Failure to accumulate the specialized cells is a likely reason why diabetic foot ulcers, like other chronic wounds, cannot get past the inflammatory phase. The results suggest that finding a way to boost the activity of FOXM1 might lead to a treatment for diabetic foot ulcers, and possibly other chronic wounds.

Morasso and Tomic-Canic agree that this study is a launching pad for multiple approaches. Going forward, the researchers aim to further their understanding of the molecular underpinnings of the disease, analyze clinical outcomes, and eventually translate their discoveries into new therapies for diabetic foot ulcers.

This work was supported by the NIH Bench-to-Bedside award made possible by the NIH Office of Clinical Research, NIAMS (ZIA-AR041124), National Institute of Nursing Research (R01-NR015649, R01-NR01388), National Institute of Diabetes and Digestive and Kidney Diseases (U01-DK119085, RC1-DK086364), and University of Miami.

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Deregulated immune cell recruitment orchestrated by FOXM1 impairs human diabetic wound healing. Sawaya AP, Stone RC, Brooks SR, Pastar I, Jozic I, Hasneen K, O'Neill K, Mehdizadeh S, Head CR, Strbo N, Morasso MI, Tomic-Canic M. Nat Commun. 2020 Sep 16;11(1):4678. doi: 10.1038/s41467-020-18276-0. PMID: 32938916.