Altered Mechanosensing by Oral Mucosal Fibroblasts Inhibits the Myofibroblast Transition

项目总结/摘要 与真皮不同，口腔是一个特权愈合的部位，不会留下明显的疤痕。基于有限 数据，口腔粘膜伤口愈合已被建议作为探索哺乳动物再生的模型。在 特别地，与真皮成纤维细胞相比，口腔粘膜成纤维细胞表现出独特的特性 这表明这些细胞被编程以促进无疤痕愈合。许多相似之处已经被描绘出来 在口腔粘膜和胎儿皮肤之间，也可以愈合而不形成疤痕。口腔黏膜成纤维细胞 与胎儿真皮成纤维细胞共有几个特征，这些特征已被认为是 无疤痕修复哺乳动物胎儿损伤皮肤无瘢痕愈合而肌成纤维细胞不参与 这表明较小的细胞力有助于再生修复。体内和体外研究表明， 胎儿成纤维细胞具有有助于无瘢痕愈合的独特特征，包括改变反应， ECM刚性和有缺陷的信号通路。然而，口腔粘膜成纤维细胞是否也 表现出这种独特的表型，并表现出对环境机械因素的不同反应， 在出生后或“成人”皮肤成纤维细胞中诱导肌成纤维细胞分化， 研究的途径，以发现新的机制，推动无疤痕愈合。因此，我们假设 口腔粘膜成纤维细胞具有内在改变的机械感测机制， 转化为肌成纤维细胞的能力。我们将在以下具体目标中检验这一假设：（1）检验 假设口腔粘膜成纤维细胞对生理生物力学刚性的反应减弱， 收缩反应和（2）确定口腔粘膜成纤维细胞的分子差异，可以靶向 减少成人真皮成纤维细胞中的肌成纤维细胞分化。我们正在采取一种创新的方法， 利用口腔粘膜成纤维细胞的机械表型作为理解再生的模型， 修复.我们将通过使用模拟不同生物基质的合成和生物基质来测试我们的新概念。 伤口愈合的机械阶段，逐渐诱导肌成纤维细胞分化，以分离 生理刚性的影响。总的来说，我们的目标是描绘潜在的分子和物理 口腔粘膜成纤维细胞可以通过定量测定ECM硬度来差异机械感知ECM硬度的机制 与组织修复相关的细胞生物力学特性。此外，我们的研究计划旨在 发现用于治疗出生后皮肤瘢痕和纤维化的新型治疗策略的潜在分子靶点 伤口愈合这些研究具有特别的临床重要性，因为没有可接受的抗纤维化治疗 皮肤瘢痕和纤维化每年花费数十亿美元用于医疗护理， 管理此外，我们提出的研究的预期结果与其他纤维化相关的 病理学以及组织工程和再生医学领域。

PROJECT SUMMARY/ABSTRACT Unlike the dermis, the oral cavity is a site of privileged healing that does not significantly scar. Based on limited data, oral mucosal wound healing has been suggested as a model for exploring mammalian regeneration. In particular, oral mucosal fibroblasts exhibit unique characteristics when compared to dermal fibroblasts suggesting that these cells are programmed to facilitate scarless healing. Many parallels have been drawn between the oral mucosa and fetal skin which can also heal without scar formation. Oral mucosal fibroblasts share several characteristics with fetal dermal fibroblasts which have been recognized as a key component of scarless repair. Injured skin in the mammalian fetus heals scarlessly without myofibroblast involvement suggesting that smaller cellular forces contribute to regenerative repair. In vivo and in vitro studies have shown that fetal fibroblasts have unique characteristics that contribute to scarless healing including altered responses to ECM rigidity and defective signaling pathways. However, it is unknown whether oral mucosal fibroblasts also demonstrate this distinct phenotype and exhibit differential responses to environmental mechanical factors that induce myofibroblast differentiation in postnatal or “adult” dermal fibroblasts which would represent a novel avenue of research for uncovering new mechanisms that drive scarless healing. Therefore, we hypothesize that oral mucosal fibroblasts have intrinsically altered mechanosensing mechanisms that limit their ability to transition into myofibroblasts. We will test this hypothesis in the following Specific Aims: (1) test the hypothesis that oral mucosal fibroblasts respond to physiologic biomechanical rigidities with an attenuated contractile response and (2) identify molecular differences in oral mucosal fibroblasts that can be targeted to reduce myofibroblast differentiation in adult dermal fibroblasts. We are taking an innovative approach by utilizing the mechanical phenotype of oral mucosal fibroblasts as a model for understanding regenerative repair. We will test our novel concept by using synthetic and biological substrates that mimic the different mechanical stages of wound healing that progressively induce myofibroblast differentiation to isolate the effects of physiologic rigidities. Overall, our goal is to delineate the underlying molecular and physical mechanisms by which oral mucosal fibroblasts may differentially mechanosense ECM rigidity by quantifying cellular biomechanical properties relevant to tissue repair. Furthermore, our research plan is designed to uncover potential molecular targets for novel treatment strategies for dermal scarring and fibrosis in postnatal wound healing. These studies are of particular clinical importance since no acceptable anti-fibrotic therapies currently exist and dermal scarring and fibrosis costs billions of dollars of year in medical care and management. In addition, the expected outcomes of our proposed studies are relevant to other fibrosis-related pathologies as well as to the fields of tissue engineering and regenerative medicine.