Scarless wound healing...

Research Article

WOUND HEALING

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Growth arrest specific–6 and angiotoxin receptor–like signaling drive oral regenerative wound repair

Michelle F. Griffin https://orcid.org/0000-0002-2027-547X, Jessica Cook https://orcid.org/0000-0002-1619-8758, AnnahMorgan https://orcid.org/0009-0006-9417-6526, Dario Boffelli https://orcid.org/0000-0003-2529-9056, MauricioDowner, Amanda F. Spielman https://orcid.org/0000-0001-9262-722X, Nicholas J. Guardino https://orcid.org/0000-0001-8577-8038, Jason L. Guo, Jennifer B. L. Parker https://orcid.org/0000-0003-2206-4120, [...] , and Michael T. Longakerhttps://orcid.org/0000-0003-1430-8914+7 authors Authors Info & Affiliations

Science Translational Medicine

2 Jul 2025

Vol 17, Issue 805

DOI: 10.1126/scitranslmed.adk2101

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Editor's summary

Mouth wounds usually heal without scarring. Mechanisms of regenerative wound healing in the oral mucosa are not fully understood. Griffin et al. compared oral mucosal cells with facial skin cells in mice to find that growth arrest specific–6 (GAS6) and angiotoxin receptor–like (AXL) signaling suppress fibrosis signaling. Inhibiting AXL in the mouse oral mucosa led to scarring after wounding and activation of focal adhesion kinase (FAK). Using GAS6 to stimulate AXL in mouse facial skin led to wounds that healed with less scarring. In rare human oral scars due to repeated injury, GAS6, AXL, and FAK were each present in amounts similar to scarred facial skin, showing that these proteins regulate scar formation similarly in different skin types. Together, these data show that AXL signaling promotes regenerative wound healing, indicating that GAS6-stimulated AXL signaling may be a therapeutic target for limiting fibrosis in scarring. —Brandon Berry

Abstract

Rapid and scarless wound repair is a hallmark of the oral mucosa, yet the cellular and molecular mechanisms that enable this regeneration remain unclear. By comparing populations of murine oral mucosal fibroblasts (OMFs) and facial skin fibroblasts (FSFs), we have identified mechanisms that facilitate regeneration over fibrosis. We found that OMFs used growth arrest specific–6 (GAS6)–angiotoxin receptor–like (AXL) signaling to suppress fibrosis-related mechanosignaling through focal adhesion kinase (FAK) in vitro. Inhibition or knockdown of AXL in the murine oral mucosa resulted in fibrotic wounds and increased activation of FAK. Stimulation of AXL by exogenous GAS6 in the murine facial skin yielded wounds that healed regeneratively as assessed by collagen deposition and organization. Rare human oral scars that resulted from repetitive injury showed decreased expression of GAS6 and AXL and increased FAK. Activating AXL by exogenous GAS6 in repetitively injured mouse oral tissue resulted in better wound healing outcomes and reduced scarring. Altogether, we show that AXL signaling is necessary for murine regenerative wound healing in the oral mucosa and sufficient to limit facial skin fibrosis.