Pathways to Rapid Wound Repair Open Door to Improved Healing

Wounds in the mouth heal with lightening speed compared to those in the skin. Now researchers have found that cells in the oral cavity are primed and ready for repair with key molecules set to go at all times. The authors suggest that if they can replicate these patterns in skin, they could speed the healing process and reduce scarring in much slower-to-heal skin wounds.

“The priming of the oral cavity allows the cells to respond very rapidly to the wound and trigger a rapid closure while the cells in the skin must first activate these mechanisms to be able to effectively close the wound,” senior author Maria Morasso, PhD, from the National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, told Medscape Medical News in an email. “This might be the reason why skin wounds heal more slowly compared with oral wounds,” she added.

To understand the healing process in the oral cavity versus the skin, the researchers induced wounds in the oral buccal mucosa and on the skin of 30 healthy volunteers. As the wounds healed over the next 6 days, the team took baseline and serial paired biopsies from the mouth and skin wounds to characterize the repair processes using RNA sequencing.

“Analysis of the healing time course revealed that oral wounds resolved significantly faster than skin wounds (P < .001),” researchers write in an article published online July 25 in Science Translational Medicine.

Samples taken from the mouth show that cells in oral wounds have distinct gene expression patterns, including a downregulation of inflammatory pathways. By contrast, sustained activation of inflammatory pathways in skin cells likely contributes to scar formation, the researchers note.

The team also found that cells in the oral mucosa expressed higher levels of key transcription factors that regulate gene expression. “Specifically, we identified transcriptional factors such as SOX2 (sex-determining region Y-box 2) and PITX1 (paired-like homeodomain 1) as having important roles in conferring special wound healing capabilities to the oral mucosa,” Morasso elaborated.

When the researchers engineered mice that overexpressed one of these transcription factors, SOX2, in the outer layer of the skin, they found that cutaneous wound healing was much more rapid than similar wounds in control mice.

“Our data indicate that the unique environment of the oral cavity represents a wound healing program geared toward rapid wound resolution,” first author Ramiro Iglesias-Bartolome, PhD, also from the Laboratory of Skin Biology at the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and colleagues write.

“Our study provides a proof-of-concept that skin cells can be reprogrammed to show increased migration and wound healing ability by shifting them to a phenotype resembling oral cells,” Morasso said in a press statement. She notes that there is an urgent need to develop more effective approaches to accelerate healing of skin wounds, given the global rise of chronic and nonhealing wounds, especially in patients with diabetes.

“By better understanding the mechanisms utilized during oral ‘ideal’ wound healing, effective treatments for chronic nonhealing wounds can be developed,” Morasso continued. “Our findings will enable us to explore this route and identify ways in which skin cells can be pharmacologically targeted to achieve increased wound healing.”

Good Step Forward

Asked by Medscape Medical News to comment on the findings, Andrew Boulton, MD, professor of medicine at the University of Manchester, United Kingdom, and visiting professor at the University of Miami in Florida, noted that the study is a good step forward. However, the findings may not apply to diabetic wounds, which are chronic and therefore different in nature than acute wounds.

“We’ve all known that oral wounds heal quickly, and the fact that researchers have shown that specific transcription factors are different in the two areas, especially SOX2 and PITX1, is very interesting,” Boulton said.

“They clearly showed that if you overexpressed some of these factors in mice, there is more rapid healing in the skin, but again, these are acute wounds,” he emphasized.

He said another feature that sets diabetic wounds apart from the acute ones studied by Iglesias-Bartolome and colleagues is the loss of sensation. “Most patients with diabetic foot wounds have lost the ‘gift of pain‘,” Boulton explained.

This means that patients with diabetic food wounds, especially those of the neuropathic variety, simply don’t have the protection or “gift” of pain, as those without diabetes. An inability to feel pain allows patients to keep walking on a foot wound, such that it is repeatedly retraumatized, which prevents healing. “A foot ulcer will only heal if you permit it to heal, and you can only permit something to heal if you don’t put pressure on it,” Boulton explained.

“So I’m not criticizing the study at all, but we have to ask, ‘Do their findings translate from an acute wound in the mouse or an acute wound in a nonweight-bearing area in a human without diabetes to a chronic wound in diabetes?” he said. Even if they do, “patients with diabetic wounds still will need protection as off-loading will always remain important,” he added.

The authors and Boulton have reported no relevant financial relationships.

Sci Transl Med. 2018;10:eaap8798. Abstract

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