Gas6-Axl signaling drives oral regenerative wound repair

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 oral mucosal fibroblasts (OMFs) and facial skin fibroblasts (FSFs), we have identified the mechanisms that facilitate regeneration over fibrosis. We found that OMFs utilize Growth arrest specific-6 (GAS6)-AXL signaling to suppress fibrosis-related mechanosignaling via Focal adhesion kinase (FAK). Inhibition and knockdown of AXL in the oral mucosa resulted in fibrotic wounds and increased activation of FAK. At the same time, stimulation of AXL in the facial skin yielded wounds that heal regeneratively. Rare human oral scars that resulted from repetitive injury showed decreased expression of GAS6/AXL and increased FAK. Activating AXL in repetitively injured mouse oral tissue resulted in better wound healing outcomes and reduced scarring. Together, our work demonstrates that AXL signaling is necessary for regenerative wound healing in the oral mucosa and sufficient to limit facial skin fibrosis. Overall design: Mouse wound tissue transcriptomes were profiled using single cell RNA sequencing, Visium spatial transcriptomics, and bulk RNA quencing. Tissue from wounds in oral mucosa and facial skin were compared. Timepoints include unwounded skin and oral mucosa, postoperative (POD) 2, 4, and 7.