Altered Mechanosensing by Oral Mucosal Fibroblasts Inhibits the Myofibroblast Transition

项目摘要/摘要 与真皮不同，口腔是一个可以特权愈合的部位，不会留下明显的疤痕。基于有限的 数据显示，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……里面 特别是，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征。 这表明这些细胞被编程为促进无疤痕愈合。有很多相似之处 在口腔粘膜和胎儿皮肤之间，也可以愈合，不会形成疤痕。口腔粘膜成纤维细胞 与胎儿真皮成纤维细胞有几个共同的特征，它们被认为是 无疤痕修复。哺乳动物胎儿受损皮肤无瘢痕愈合，无肌成纤维细胞参与 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独特的特性，有助于无疤痕愈合，包括改变反应 到细胞外基质僵化和信号通路缺陷。然而，目前尚不清楚口腔粘膜成纤维细胞是否也 表现出这种独特的表型，并对环境机械因素表现出不同的反应 诱导生后或成年真皮成纤维细胞分化为肌成纤维细胞是一种新的 发现无疤痕愈合的新机制的研究之路。因此，我们假设 口腔粘膜成纤维细胞内在地改变了机械传感机制，限制了它们的 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说：(1)检验 口腔黏膜成纤维细胞对生理生物力学僵硬反应减弱的假说 收缩反应和(2)确定口腔粘膜成纤维细胞的分子差异可作为靶点 减少成人真皮成纤维细胞中肌成纤维细胞的分化。我们正在采取创新的方法，通过 利用口腔黏膜成纤维细胞的机械表型作为理解再生的模型 修理。我们将通过使用合成和生物底物来测试我们的新概念，这些底物模仿不同的 伤口愈合的机械阶段，逐步诱导肌成纤维细胞分化以分离 生理僵硬的影响。总体而言，我们的目标是描绘出潜在的分子和物理 口腔黏膜成纤维细胞通过量化差异机械感知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 为出生后皮肤瘢痕和纤维化的新治疗策略发现潜在的分子靶点 伤口愈合。这些研究具有特别重要的临床意义，因为尚无可接受的抗纤维化治疗方法。 目前存在的皮肤疤痕和纤维化每年花费数十亿美元的医疗和 管理层。此外，我们建议的研究的预期结果也与其他与纤维化相关的研究有关。 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.