The human mouth possesses a remarkable ability to heal wounds swiftly and without scarring, a phenomenon that has long intrigued scientists seeking to understand the underlying biological mechanisms. Recent groundbreaking research conducted through a collaboration between Cedars-Sinai, Stanford Medicine, and the University of California, San Francisco (UCSF) has uncovered key molecular signals responsible for this rapid and scarless oral tissue regeneration. Published in the prestigious journal Science Translational Medicine, the study provides new insights that may revolutionize the future treatment of skin wounds, aiming to reduce or eliminate scarring on various parts of the body.

Unlike skin wounds which may take weeks to heal and often leave permanent scars, injuries to the oral mucosa—the lining inside the mouth—typically resolve within a few days without any residual marks. This remarkable contrast prompted the researchers, led by Ophir Klein, MD, PhD, and Michael Longaker, MD, to dissect the biological differences that drive these divergent healing responses. Their goal was not merely academic: by mapping the molecular pathways that enable scarless healing in the mouth, they hope to engineer therapies to improve skin wound repair.

The team focused their investigation on cellular signaling molecules within the oral mucosa and skin tissues of laboratory mice, leveraging advanced molecular biology and imaging techniques. They identified the involvement of a signaling axis centered on the growth arrest-specific protein 6 (GAS6) and the tyrosine kinase receptor AXL. This pathway emerged as a crucial regulator blocking the activation of focal adhesion kinase (FAK), a protein known to promote fibrosis and scar tissue formation in skin wounds. The discovery hinges on the concept that inhibitory signals from GAS6-AXL can prevent the typically fibrotic wound healing process.

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Through experimental manipulation, the researchers demonstrated that pharmacologically inhibiting the AXL receptor in the oral mucosa impaired its ability to heal rapidly and scarlessly, causing the wounds to behave more like conventional skin wounds. Conversely, activating or stimulating AXL in skin wounds led to enhanced regenerative outcomes with reduced scarring, mimicking the superior healing environment naturally present in oral tissues. These results underscore the therapeutic potential of modulating this pathway to influence tissue repair.

One of the study’s most striking revelations is the idea that signaling pathways inherent to the oral mucosa actively suppress the pro-fibrotic cascade generally initiated following skin injury. Whereas skin wounds often activate FAK signaling to stimulate fibroblast proliferation and collagen deposition forming scars, the GAS6-AXL signaling axis provides a counter-regulatory brake. This new understanding challenges prior assumptions that scarring is an inevitable side effect of wound healing, suggesting instead that it is a modifiable biological process.

The researchers emphasize that the GAS6 ligand’s binding to AXL receptor tyrosine kinase initiates intracellular signaling events that modulate cell behavior in the wound microenvironment, influencing epithelial cell migration and extracellular matrix remodeling favorably. By preventing excessive activation of FAK-mediated pathways, this signaling allows for regeneration of tissue architecture without pathological fibrosis. These findings build on a growing body of evidence that regenerative healing involves precisely orchestrated cellular communications.

Despite the promise revealed in this preclinical mouse model, the study authors caution that translating these results into human therapies requires further investigation. Human skin and oral tissues share similarities but also distinct differences in their microenvironment and immune responses. Future clinical studies will be necessary to validate the role of GAS6-AXL signaling in human wound healing and to explore potential pharmaceutical agents or gene therapies that can harness this mechanism.

Dr. Ophir Klein, co-corresponding author and expert in pediatric regenerative medicine, highlights the broad implications of their findings: “If we can understand why the mouth heals without scarring and then safely apply those lessons to skin wounds, we could potentially transform outcomes for patients suffering from injuries, surgeries, or chronic wounds with disfiguring scars.” Such advances could benefit not only cosmetic concerns but also improve functional recovery in burn victims and reconstructive surgery patients.

The importance of reducing scar formation extends beyond aesthetics; scars can restrict mobility, impair organ function, and contribute to significant psychological distress. Current clinical treatments for scarring are limited and largely reactive, often addressing symptoms rather than underlying causes. The ability to proactively modulate wound healing at the molecular level represents a major paradigm shift, inspiring new therapeutic avenues to promote regenerative over fibrotic responses.

Supporting the rigor of this multi-institutional study is an extensive funding network including the National Institutes of Health and various foundations. These resources facilitated high-resolution molecular analyses and experimental models essential to dissecting the complex interplay between signaling proteins like GAS6, AXL, and FAK. The research exemplifies how interdisciplinary collaborations accelerate discovery in regenerative medicine and dermatology.

Looking ahead, the team intends to delve deeper into the molecular mechanisms governing GAS6-AXL interactions, exploring how the signaling cascade influences other cell populations such as immune cells and mesenchymal stromal cells in the wound niche. They also aim to develop targeted therapies that can precisely activate or mimic this pathway’s effects in human skin, potentially involving biologics or small molecule drugs that balance healing and scar prevention.

Ultimately, this research opens an exciting frontier in understanding the biology of wound repair, blending fundamental cellular signaling knowledge with translational aspirations. By unlocking the secrets behind the mouth’s unique regenerative powers, scientists move closer to a future where scarless healing is not just a clinical curiosity but a widely attainable medical reality. Such breakthroughs underscore the promise of modern biomedical research to transform pain, injury, and recovery for millions worldwide.

Subject of Research: Mechanisms of scarless wound healing and regenerative repair in oral mucosa versus skin

Article Title: Growth arrest specific-6 and angiotoxin receptor-like signaling drives oral regenerative wound repair

News Publication Date: 2-Jul-2025

Web References: http://dx.doi.org/10.1126/scitranslmed.adk2101

References: Published in Science Translational Medicine

Keywords: Wound healing, Cell biology, Oral mucosa, GAS6, AXL receptor, FAK signaling, Scarless healing, Tissue regeneration

Tags: biological pathways of scar formationCedars-Sinai research collaborationcellular signaling in wound healinghealing responses in oral mucosamolecular mechanisms of healingoral wound healingpreclinical study on wound repairscarless tissue regenerationskin wound treatment innovationsStanford Medicine findingstranslational medicine in wound careUCSF scientific contributions