Altered Mechanosensing by Oral Mucosal Fibroblasts Inhibits the Myofibroblast Transition

口腔粘膜成纤维细胞改变机械感应抑制肌成纤维细胞转变

• 批准号: 9809631
• 负责人: Aron Parekh
• 金额: $ 21.25万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9809631
• 关键词: 3-Dimensional; Adhesions; Adult; Attenuated; Beds; Behavior; Biochemical; Biological; Biological Assay; Biomechanics; Biophysical Process; Caring; Cells; Characteristics; Cicatrix; Clinical; Contracts; Cues; Data; Dermal; Dermis; Environmental Risk Factor; Exhibits; Extracellular Matrix; Fetus; Fibroblasts; Fibrosis; Focal Adhesions; Fostering; Generations; Genetic Transcription; Goals; Harvest; High-Throughput Nucleotide Sequencing; Human; In Vitro; Injury; Lead; Mechanical Stress; Mechanics; Medical; Modeling; Molecular; Molecular Target; Myofibroblast; Natural regeneration; Ontology; Oral; Oral cavity; Oral mucous membrane structure; Outcome; Pathology; Phenotype; Physiological; Property; RNA; Regenerative Medicine; Regenerative response; Research; Signal Pathway; Site; Skin; Statutes and Laws; Testing; Therapeutic; Tissue Engineering; Transforming Growth Factors; Variant; Work; Wound Healing; analog; base; cost; design; fetal; genetic signature; healing; human fetus tissue; in vivo; injured; innovation; mechanical force; mechanotransduction; novel; postnatal; postnatal human; regenerative; repaired; response; tissue regeneration; tissue repair; transcriptome sequencing; treatment strategy; wound; 3-Dimensional; Adhesions; Adult; Attenuated; Beds; Behavior; Biochemical; Biological; Biological Assay; Biomechanics; Biophysical Process; Caring; Cells; Characteristics; Cicatrix; Clinical; Contracts; Cues; Data; Dermal; Dermis; Environmental Risk Factor; Exhibits; Extracellular Matrix; Fetus; Fibroblasts; Fibrosis; Focal Adhesions; Fostering; Generations; Genetic Transcription; Goals; Harvest; High-Throughput Nucleotide Sequencing; Human; In Vitro; Injury; Lead; Mechanical Stress; Mechanics; Medical; Modeling; Molecular; Molecular Target; Myofibroblast; Natural regeneration; Ontology; Oral; Oral cavity; Oral mucous membrane structure; Outcome; Pathology; Phenotype; Physiological; Property; RNA; Regenerative Medicine; Regenerative response; Research; Signal Pathway; Site; Skin; Statutes and Laws; Testing; Therapeutic; Tissue Engineering; Transforming Growth Factors; Variant; Work; Wound Healing; analog; base; cost; design; fetal; genetic signature; healing; human fetus tissue; in vivo; injured; innovation; mechanical force; mechanotransduction; novel; postnatal; postnatal human; regenerative; repaired; response; tissue regeneration; tissue repair; transcriptome sequencing; treatment strategy; wound

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.

项目摘要/摘要 与真皮不同，口腔是一个没有明显疤痕的特权康复场所。基于有限 数据是口服粘膜伤口愈合，作为探索哺乳动物再生的模型。在 与皮肤成纤维细胞相比，特别的口服粘膜成纤维细胞具有独特的特征 建议对这些细胞进行编程以促进无疤的愈合。许多相似之处已被绘制 在口腔粘膜和胎儿皮肤之间，也可以在不形成疤痕的情况下愈合。口服粘膜成纤维细胞 与胎儿皮肤成纤维细胞共享几个特征，这些特征已被认为是被认为是的关键组成部分 无疤的维修。哺乳动物胎儿受伤的皮肤无毛，无肌纤维细胞参与 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征，可导致无疤的愈合，包括改变反应 到ECM刚度和有缺陷的信号通路。但是，尚不清楚口服粘膜成纤维细胞 证明这种独特的表型和对环境机械因素的差异反应 在产后或“成人”皮肤成纤维细胞中诱导肌纤维细胞分化，这将代表一种新颖 研究的研究途径，以揭示带来无疤痕愈合的新机制。因此，我们假设 口服粘膜成纤维细胞具有内在改变的机制，以限制其 过渡到肌纤维细胞的能力。我们将在以下特定目的中检验该假设：（1）测试 口服粘膜成纤维细胞对生理生物力学刚性有反应的假设 收缩反应和（2）确定可以针对的口服粘膜成纤维细胞的分子差异 减少成年皮肤成纤维细胞中的肌纤维细胞分化。我们正在采取一种创新的方法 利用口服粘膜成纤维细胞的机械表型作为理解再生的模型 维修。我们将通过使用模仿不同的合成和生物基底物来测试我们的新概念 伤口愈合的机械阶段，逐渐诱导肌纤维细胞分化以分离 身体僵化的影响。总体而言，我们的目标是描述基础分子和物理 口服粘膜成纤维细胞可能通过量化而对ECM刚度有所不同的机制 与组织修复有关的细胞生物力学特性。此外，我们的研究计划旨在 发现潜在的分子靶标，用于新的治疗策略，用于产后皮肤疤痕和纤维化 伤口愈合。由于没有可接受的抗纤维化疗法，因此这些研究特别重要 目前存在，皮肤疤痕和纤维化成本数十亿美元的医疗服务和 管理。此外，我们提出的研究的预期结果与其他纤维化有关 病理学以及组织工程和再生医学领域。