Microscope image showing fibroblasts (as red lines) with their nuclei (as blue circles) taking up oral sEVs (as green dots)

Fibroblasts (red lines with blue nuclei) are tested to see whether they can take up oral small extracellular vesicles (sEVs; green dots) as part of research into oral healing conducted by Phil Stephens, a cell biologist at Cardiff University, UK.Credit: Rob Knight

At the US National Institutes of Health in Bethesda, Maryland, 30 healthy people prepared to be hurt. Researchers punched out a 3-millimetre-deep circular biopsy from the volunteers’ inner cheeks. They repeated the process on the skin just below the armpit. Somehow, the scientists convinced the participants to come back to the laboratory for observation. The difference between the two injury sites was striking. The mouth cuts closed quickly — in a few days. But the inner arm wounds were still lingering two weeks later1.

The results, reported in 2018, were not unexpected. Scientists have long known that oral tissue repairs itself quicker than skin. “You cut your skin and it takes over a week to heal,” says skin biologist Maria Morasso at the National Institute of Arthritis, Musculoskeletal and Skin Diseases in Bethesda, who led the experiment. “If you bite your cheek, it might hurt a lot but the next day you can’t even find the injury.” Swift mending is clearly useful in the oral cavity, where chewing would further irritate an injury. Plus, the mouth is full of bacteria and other microbes, which could thrive in crevices. There was a rationale for (mildly) injuring the study participants in Bethesda, however. Uncovering the mouth’s curative secrets might help medics to treat chronic wounds and even halt the unwanted side effects that occur when skin heals normally.

For some people, skin healing can slow to a crawl. Lesions that fail to repair in a timely manner affect an estimated 6.5 million people in the United States alone. These wounds represent a huge burden on health-care systems. Ageing increases the risk of chronic wounds, as do diabetes and obesity. The challenge of treating unhealing wounds is therefore only set to grow in ageing populations with rising rates of type 2 diabetes.

A scar is born

On the other side of the skin-healing coin is scarring. Pretty much everyone has a scar somewhere on their body, but some are more distressing than others. For people who have undergone major surgery or experienced a bad burn on an especially visible part of their body, such as the face, the scars left behind can lead to stigmatization. Other severe scars can cause functional impairment. But oral wounds usually heal without a trace.

There is an evolutionary reason for this, says Phil Stephens, a cell biologist at Cardiff University, UK. “If you’re a caveman or woman with a big wound on your arm, sure it’s going to scar,” he says. “But if the scar is in your mouth and you can’t eat — that’s it, you’re a goner.” Stephens explains that connective tissue cells called fibroblasts drive healing by depositing a plug of structural support material into the wound bed. In the skin, this extracellular matrix is laid down shoddily, resulting in scar tissue. In the mouth, on the other hand, the extracellular matrix blends seamlessly into the surrounding tissue, as if there had never been a dent.

Comparison biopsy images - oral at left and underarm at right

Biopsies of oral (left) and skin (right) tissue were taken as part of the US National Institutes of Health study into comparative healing at different injury sites on the body.Credit: NIDCR (go.nature.com/3ficpu9)

Specialists initially assumed that the mouth’s superior healing capabilities must have something to do with the oral environment. Perhaps, as some scientists suggested, saliva was priming the oral mucosa (the soft tissue lining inside the mouth) for recovery. Growth factors in saliva are still likely to play a part, says dental researcher Luisa DiPietro at the Center for Wound Healing and Tissue Regeneration at the University of Illinois in Chicago. But the tide began to turn in the mid-1990s as researchers learnt that even cells isolated from the oral environment behaved differently from skin cells. In recent years, genomic analysis has thrown up more clues. “Histologically, the cells look very similar in skin and oral mucosa, but they really are different genetically,” says DiPietro.

The mouth’s blueprint for healing is not infallible. DiPietro actually has a small scar on her inner cheek — the relic of a cycling accident in her teenage years that knocked out several teeth. “When you have a lot of damage, all bets are off,” she says. Nevertheless, she is fascinated by the mechanisms that guide near-perfect tissue regrowth in the oral cavity. One of her group’s first notable discoveries was that inflammation is suppressed in the mouth compared with the skin2. Although inflammation is essential for healing — as macrophages chomp up dead cells and secrete molecules that promote repair — DiPietro says it typically goes overboard in skin. “This may be an insurance policy against infection, but at the expense of some resultant tissue damage,” she says.

DiPietro’s group also noticed something strange about the blood vessels that form when oral tissue is injured compared with skin. Angiogenesis, in which blood vessels form to supply oxygen and other nutrients to the injury, usually aids healing. But in the mouth, the researchers found that fewer blood vessels sprouted in response to a wound. This might seem paradoxical, but the team also saw that the vessels that did grow in the mouth matured more quickly than those in the skin3. As is the case with inflammation, DiPietro says, it seems that angiogenesis is too enthusiastic in the skin following injury. Although many vessels quickly form, they are not good quality. As a result, the rapid formation of new blood vessels actually slows down healing.

Chronic youth

Back in Morasso’s lab, genetic analysis of the volunteers’ biopsies gleaned intriguing results. In the oral samples, master genes associated with repair called SOX2 and PITX were switched on before the injury even happened. In the skin, the same genes weren’t activated until after the wound occurred — and even then, they were expressed at much lower levels than in the mouth. The findings suggest that the mouth is always ready to mend at a moment’s notice. “Oral tissues, at the molecular level, seem to be primed for healing,” Morasso says.

Maria Morasso smiling at the camera in a full laboratory

Maria Morasso is a skin biologist at the National Institute of Arthritis, Musculoskeletal and Skin Diseases in Bethesda, Maryland.Credit: NIH

All these differences between oral and skin healing might be down to their embryonic origins, says anatomist Tanya Shaw at King’s College London. Oral tissue is derived from embryonic cells called the neural crest. By contrast, connective tissue cells underneath the skin’s surface originate from a different germ layer called the mesoderm. “There’s a little bit of evidence that neural crest cells are less immune-reactive so may somehow work to dampen the inflammatory response,” Shaw says. And the similarities between oral mucosa and fetal tissue, which also heals rapidly, without scarring, are hard to deny. The shared traits suggested a possible anti-ageing mechanism in the mouth.

So, could the oral cavity be a fountain of youth? Over a decade ago, Stephens and colleagues compared oral cells with skin cells from the same patients and discovered mouth tissue really was younger at the molecular level. The oral mucosal cells’ chromosomes had longer telomeres — non-coding repetitive sequences that deplete over time4. Shortly afterwards, Stephens and other Cardiff researchers found the likely explanation. The mouth is home to stem-cell-like communities called oral mucosal lamina progenitor cells5 which can make different tissue types. These cells aren’t just forever young, says Stephens, they are also potently immunosuppressive and antibacterial — more factors that could explain the mouth’s regenerative powers.

On the mend

The discovery of several potential mechanisms behind oral tissue’s accelerated healing capabilities raises the possibility of better treatments for chronic wounds and scarring. Perhaps anti-angiogenic treatments used in cancer could be adapted to prevent scars forming after surgery. Similarly, therapies that switch on the master-healing genes that are always active in the oral mucosa might help chronic skin wounds to repair themselves. Indeed, when Morasso bred mice to overexpress SOX2 in their skin cells, the animals healed faster than normal.

Stephens is dubious about skin therapies that target just one pathway, though. When researchers have gone down this road in the past to reduce scarring, it has not worked out. Ten years ago, there was much excitement around Justiva (avotermin) — genetically engineered transforming growth factor β3 (TGF-β3) — which researchers at the University of Manchester, UK, identified as a facilitator of skin healing in animals. Early clinical trials in humans garnered promising results. But the phase III findings, announced in February 2011, sent shares in the therapy’s developer tumbling. When compared with the placebo, the treatment did not reduce the appearance of scarring.

It is not clear why the therapy failed at the final hurdle, but Stephens thinks that targeting only the TGF-β signalling pathway (which has been found to regulate wound healing) was not enough to stop the body producing a scar — another, less well-understood biochemical cascade could have stepped in. “If you go after one molecule, it’s very unlikely to work,” says Stephens. “There will be compensation by some other molecule or another pathway.”

It might be possible to get around that problem by treating a scar or chronic wound with a package of chemicals the mouth uses for repair, he suggests. Applying oral cells directly to the injured tissue is one option. But there are hurdles, such as the high cost of cell treatment and the likelihood that the body will reject the foreign material.

A better bet, Stephens thinks, is to use not the cells themselves but rather the molecules they secrete. The Cardiff team’s preliminary findings6, alongside separate research led by scientists at the University of Pennsylvania in Philadelphia7, suggest that lipid nanoparticle beads called exosomes are secreted from the oral stem cells and drive the healing process, while repelling microbes. Stephens’ hope is that a topical preparation containing these vesicles will reduce scarring, speed the recovery of hard-to-heal wounds, and prevent cuts from succumbing to infection. But before human trials can happen, the theory will first have to be proved in animal models — ideally in pigs, which have skin that is anatomically similar to that of humans. Even then, researchers still won’t know exactly what these therapeutic parcels contain without further work.

Clinically approved skin therapies based on oral-healing models might still be a way off, but DiPietro is excited that several research groups are now pursuing this niche field. Her ultimate dream is that digging into the mouth’s knack for repair will lead to treatments that not only help skin wounds to close without scarring but also allow humans to rapidly regenerate skin after it is lost — similar to a salamander regrowing its limbs. “The oral mucosa holds this tremendous hope that humans have the capability to heal very regeneratively,” she says. “I think it really could be key.”