Laboratory of Skin Biology, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD 20892, USA.
Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, Bethesda, MD 20892, USA.
Sci Transl Med. 2018 Jul 25;10(451). doi: 10.1126/scitranslmed.aap8798.
Oral mucosal wound healing has long been regarded as an ideal system of wound resolution. However, the intrinsic characteristics that mediate optimal healing at mucosal surfaces are poorly understood, particularly in humans. We present a unique comparative analysis between human oral and cutaneous wound healing using paired and sequential biopsies during the repair process. Using molecular profiling, we determined that wound-activated transcriptional networks are present at basal state in the oral mucosa, priming the epithelium for wound repair. We show that oral mucosal wound-related networks control epithelial cell differentiation and regulate inflammatory responses, highlighting fundamental global mechanisms of repair and inflammatory responses in humans. The paired comparative analysis allowed for the identification of differentially expressed SOX2 (sex-determining region Y-box 2) and PITX1 (paired-like homeodomain 1) transcriptional regulators in oral versus skin keratinocytes, conferring a unique identity to oral keratinocytes. We show that SOX2 and PITX1 transcriptional function has the potential to reprogram skin keratinocytes to increase cell migration and improve wound resolution in vivo. Our data provide insights into therapeutic targeting of chronic and nonhealing wounds based on greater understanding of the biology of healing in human mucosal and cutaneous environments.
口腔黏膜伤口愈合一直被认为是一种理想的伤口愈合系统。然而，介导黏膜表面最佳愈合的内在特征还了解甚少，特别是在人类中。我们使用修复过程中的配对和顺序活检，对人类口腔和皮肤伤口愈合进行了独特的比较分析。通过分子谱分析，我们确定了在口腔黏膜的基础状态下存在伤口激活的转录网络，为伤口修复启动上皮细胞。我们表明，口腔黏膜与伤口相关的网络控制上皮细胞分化并调节炎症反应，突出了人类修复和炎症反应的基本全局机制。配对比较分析鉴定了口腔与皮肤角质细胞中差异表达的 SOX2（性别决定区 Y 盒 2）和 PITX1（成对样同源域 1）转录调节剂，为口腔角质细胞赋予了独特的身份。我们表明，SOX2 和 PITX1 的转录功能有可能重新编程皮肤角质细胞，以增加细胞迁移并改善体内伤口愈合。我们的数据为基于对人类黏膜和皮肤环境中愈合生物学的更深入了解，针对慢性和非愈合性伤口的治疗靶向提供了见解。
