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The Mechanical Phenotype of Fetal Fibroblasts as a Model for Regenerative Repair

胎儿成纤维细胞的机械表型作为再生修复模型

基本信息

批准号：
9184522
负责人：
Aron Parekh
金额：
$ 7.9万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-03-01 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9184522
关键词：
3-Dimensional Adhesions Adult Atomic Force Microscopy Automobile Driving Beds Behavior Biochemical Biomechanics Caring Cells Characteristics Cicatrix Clinical Collagen Collagen Type I Collagen Type III Contracts Cues Data Defect Deposition Dermal Disease Environmental Risk Factor Exhibits Extracellular Matrix Fetus Fibroblasts Fibrosis Focal Adhesions Gene Expression Generations Genetic Goals Granulation Tissue Harvest High-Throughput Nucleotide Sequencing Human Immunofluorescence Immunologic In Vitro Inflammation Lead Mechanical Stress Mechanics Medical Modeling Molecular Molecular Target Myofibroblast Natural regeneration Ontology Outcome Pathologic Pathology Pathway interactions Phenotype Physiological Play Population Property RNA Regenerative Medicine Regenerative response Research Role Sampling Signal Pathway Skin Smooth Muscle Actin Staining Method Stress Fibers Testing Therapeutic Tissue Differentiation Tissue Engineering Tissues Traction Transforming Growth Factors Transplantation Variant Western Blotting Work Wound Healing cost design fetal fibroblast stimulating factor-1 healing in vivo injured innovation mRNA Expression mechanotransduction novel programs public health relevance regenerative repaired response tissue repair transcriptome sequencing treatment strategy wound

项目摘要

DESCRIPTION (provided by applicant): In post-natal or "adult" dermal wound healing, fibroblasts mechanically sense ("mechanosense") rigidity and tension that develop in granulation tissue and differentiate into myofibroblasts. Myofibroblasts generate large contractile forces that excessively contract and remodel the ECM resulting in scarring and fibrosis. In contrast, 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 may contribute to scarless healing including altered responses to ECM rigidity and defective signaling pathways. However, it remains unclear why fetal fibroblasts retain this distinct phenotype and exhibit differential responses to environmental factors such as ECM rigidity that induce myofibroblast differentiation in adult fibroblasts. Therefore, our overall hypothesis is that fetal fibroblasts d not become myofibroblasts in response to physiologic biomechanical rigidities. We will test this hypothesis with the following Specific Aims: (1) to test the specific hypothesis that fetal fibroblasts have intrinsically altered mechanosensing which leads to ineffective myofibroblast differentiation, (2) to determine how matrix composition influences myofibroblast differentiation since adult and fetal wound healing are characterized by different types of collagen, and (3) to use a sequencing approach to identify molecular differences in fetal fibroblast gene expression that can be used to target myofibroblast differentiation in adult fibroblasts. We are taking an innovative approach by utilizing the mechanical phenotype of fetal fibroblasts as a model for understanding regenerative repair since these cells appear to lack the ability to produce larger cellular forces in response to matrix rigidity which contribute to myofibroblast differentiation an fibrotic healing. We will test our novel concept by using synthetic substrates that mimic the different mechanical stages of wound healing that progressively induce myofibroblast differentiation to isolate the effects of physiologic rigidities and different ECM components. Overall, our goal is to delineate the underlying molecular and physical mechanisms by which fetal fibroblasts differentially mechanosense ECM rigidity by quantifying cellular biomechanical properties relevant to dermal tissue repair. Furthermore, our research plan is designed to uncover potential molecular targets for novel treatment strategies for dermal scarring and fibrosis in post-natal wound healing. These studies are of particular clinical importance since no acceptable anti-fibrotic therapies currently exist and dermal scarring and fibrosis costs billions f 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.

描述(申请人提供)：在出生后或“成人”皮肤伤口愈合过程中，成纤维细胞机械感觉(“机械感觉”)肉芽组织中形成的僵硬和张力，并分化为肌成纤维细胞。肌成纤维细胞产生较大的收缩过度收缩和重塑ECM的力量，导致瘢痕和纤维化。相比之下，哺乳动物胎儿受伤的皮肤在没有肌成纤维细胞参与的情况下可以无痕愈合，这表明较小的细胞力量有助于再生修复。体内和体外研究表明，胎儿成纤维细胞具有独特的特性，可能有助于无瘢痕愈合，包括对ECM僵硬和信号通路缺陷的反应改变。然而，目前尚不清楚为什么胎儿成纤维细胞保留了这种独特的表型，并对环境因素(如ECM刚性)表现出不同的反应，这些因素诱导成人成纤维细胞分化为肌纤维细胞。因此，我们的总体假设是胎儿成纤维细胞不会因为生理生物力学的僵硬而变成肌成纤维细胞。我们将通过以下具体目标来检验这一假说：(1)检验胎儿成纤维细胞内在地改变机械感觉从而导致肌成纤维细胞分化的特定假说，(2)确定基质成分如何影响肌成纤维细胞分化，因为成人和胎儿伤口愈合具有不同类型的胶原的特征，以及(3)使用测序方法确定可用于靶向成年成纤维细胞肌成纤维细胞分化的胎儿成纤维细胞基因表达的分子差异。我们正在采取一种创新的方法，利用胎儿成纤维细胞的机械表型作为了解再生修复的模型，因为这些细胞似乎缺乏产生更大的细胞力来响应基质刚性的能力，这有助于肌成纤维细胞的分化和纤维愈合。我们将通过使用合成底物来测试我们的新概念，这些底物模拟伤口愈合的不同机械阶段，逐步诱导肌成纤维细胞分化，以分离生理刚性和不同的ECM成分的影响。总体而言，我们的目标是通过量化与真皮组织修复相关的细胞生物力学特性来描述胎儿成纤维细胞机械感受ECM刚性的潜在分子和物理机制。此外，我们的研究计划旨在发现潜在的分子靶点，为出生后伤口愈合中真皮瘢痕和纤维化的新治疗策略提供新的治疗策略。这些研究具有特别重要的临床意义，因为目前还没有可接受的抗纤维化疗法，而且皮肤瘢痕形成和纤维化每年要花费数十亿美元的医疗护理和管理费用。此外，我们建议的研究的预期结果与其他纤维化相关的病理以及组织工程和再生医学领域有关。