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

IF 14.6 1区医学 Q1 CELL BIOLOGY

Science Translational Medicine Pub Date : 2025-07-02 DOI:10.1126/scitranslmed.adk2101

Michelle F. Griffin, Jessica Cook, Annah Morgan, Dario Boffelli, Mauricio Downer, Amanda F. Spielman, Nicholas J. Guardino, Jason L. Guo, Jennifer B. L. Parker, Michael Januszyk, Caleb Valencia, Maxwell Kuhnert, John Lu, Rachel Zwick, Derrick C. Wan, Ophir D. Klein, Michael T. Longaker

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引用次数: 0

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.

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生长阻滞特异性- 6和血管毒素受体样信号驱动口腔再生伤口修复

快速和无疤痕的伤口修复是口腔黏膜的一个标志，但细胞和分子机制，使这种再生尚不清楚。通过比较小鼠口腔黏膜成纤维细胞（OMFs）和面部皮肤成纤维细胞（fsf）的数量，我们已经确定了促进纤维化再生的机制。我们发现OMFs利用生长阻滞特异性- 6 (GAS6) -血管毒素受体样（AXL）信号通过局灶黏附激酶（FAK）抑制纤维化相关的机械信号。小鼠口腔黏膜AXL的抑制或敲低导致纤维化伤口和FAK的激活增加。外源性GAS6刺激小鼠面部皮肤中的AXL，通过胶原沉积和组织评估，产生再生愈合的伤口。在罕见的重复性损伤口腔瘢痕中，GAS6和AXL表达降低，FAK表达升高。在重复损伤的小鼠口腔组织中，外源性GAS6激活AXL可导致更好的伤口愈合结果和减少疤痕。总之，我们发现AXL信号对于小鼠口腔黏膜再生伤口愈合是必要的，并且足以限制面部皮肤纤维化。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Science Translational Medicine CELL BIOLOGY-MEDICINE, RESEARCH & EXPERIMENTAL

CiteScore

26.70

自引率

1.20%

发文量

309

审稿时长

1.7 months

期刊介绍： Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research. The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases. The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine. The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.