Probing biochemical/biophysical influences on endothelial-mesenchymal transition

探讨生化/生物物理对内皮间质转化的影响

基本信息

批准号：
8596819
负责人：
WILLIAM L. MURPHY
金额：
$ 21.51万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-01-01 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8596819
关键词：
Adult Area Biochemical Biocompatible Materials Biological Biological Phenomena Bone Diseases Cartilage Cell Adhesion Cell Culture Techniques Cell Differentiation process Cell physiology Cell-Cell Adhesion Cells Collagen Coupled Cues Development Disease Disease Progression Endothelial Cells Environment Ethylene Glycols Extracellular Matrix Fatty acid glycerol esters Fibronectins Fibrosis Growth Factor Health Heterotopic Ossification Human Hydrogels Investigation Ligands Malignant Neoplasms Mesenchymal Myofibroblast Normal tissue morphology Osteogenesis Peptides Phenotype Play Prevalence Process Property Proteoglycan Reporting Research Role Signal Transduction Skeletal Muscle System Tissues Transforming Growth Factor Beta 2 Vitronectin Work base biophysical properties bone bone morphogenetic protein 4 cell behavior cell growth cell type combinatorial density design ethylene glycol experience extracellular innovation insight laminin-10 medical implant mimetics monolayer novel progressive myositis ossificans public health relevance research study skeletal tissue therapeutic development

项目摘要

DESCRIPTION (provided by applicant): Several recent reports have demonstrated that endothelial cells can differentiate into mesenchymal cell types [1-8], a process called endothelial-mesenchymal transition (EndoMT or EndMT). In turn, endothelial cell-derived mesenchymal cells are capable of differentiating into multiple cell types, and have been shown to form fat, cartilage, and bone, respectively[8]. Recent studies indicate that EndMT contributes to disease progression in post-developmental tissue, and thorough investigations have shown roles in fibrosis[1, 3-5], cancer[2], and heterotopic ossification associated with fibrodysplasia ossificans progressiva (FOP) [8]. Therefore, the factors that influence EndMT may be of particular relevance in understanding and manipulating disease progression. The extracellular matrix (ECM) provides a wide variety of biochemical and biophysical cues that guide cell function, and several matrix components have been implicated in EndMT during tissue development, including proteoglycans [9], vitronectin, collagen, fibronectin and laminin [10-11]. In addition, TGF-b superfamily growth factors can induce EndMT[3, 8] and the influence of soluble TGF-b on endothelial cell behavior is dependent on ECM components present in culture [12]. Further, biophysical factors are also known to be important determinants of endothelial cell behavior, mesenchymal cell differentiation [13], fibrosis, and bone disease [5, 14-24]. Taken together, these previous studies implicate ECM-derived signals as likely regulators of EndMT and, in turn, disease progression. However, the role for the ECM in guiding EndMT is a largely unexplored area of research, perhaps due to the relatively recent discovery that this process occurs in adult tissue. Here, we propose an approach to identify ECM-mimetic signals that influence EndMT. The experimental approach is based on our experience creating materials to efficiently control cell-material interactions. The guiding hypothesis of the application is that biochemical and biophysical factors that mimic extracellular matrix properties will each significantly influence the process of EndMT. The proposed studies are Significant, as they will provide critical new insights into how the extracellular matrix contributes to EndMT, and the diseases in which it is implicated. The few factors that are known to influence EndMT in adult tissue (e.g., BMP-4, TGF-b1, TGF-b2) and the changes in endothelial cell phenotype that result (e.g., myofibroblast activation, heterotopic osteogenesis) are generally implicated in a range of diseases that are of substantial and broad relevance. Therefore, a better understanding of the role of EndMT could have a substantial benefit for human health. The proposed studies are Innovative, as they use novel, chemically-defined cell culture arrays to efficiently probe the effects of ECM-mimetic signals. This approach for probing ECM-mimetic signals is ideal in the case of the EndMT process, as the ECM plays a poorly understood but likely critical role in EndMT. Further, understanding how synthetic biomaterials influence EndMT could ultimately have relevance to medical implant design, particularly in scenarios in which it is important to limit fibrosis or heterotopic ossification.

描述（由申请人提供）：最近的几份报告表明，内皮细胞可以分化为间充质细胞类型 [1-8]，这一过程称为内皮-间质转化（EndoMT 或 EndMT）。反过来，内皮细胞衍生的间充质细胞能够分化成多种细胞类型，并已被证明分别形成脂肪、软骨和骨骼[8]。最近的研究表明，EndMT 有助于发育后组织的疾病进展，彻底的研究表明其在纤维化 [1, 3-5]、癌症 [2] 以及与进行性骨化性纤维发育不良 (FOP) 相关的异位骨化中发挥作用 [8] 。因此，影响 EndMT 的因素可能与理解和控制疾病进展特别相关。细胞外基质 (ECM) 提供了指导细胞功能的多种生化和生物物理线索，并且组织发育过程中的 EndMT 涉及多种基质成分，包括蛋白聚糖 [9]、玻连蛋白、胶原蛋白、纤连蛋白和层粘连蛋白 [10-11] ]。此外，TGF-b 超家族生长因子可以诱导 EndMT[3, 8]，可溶性 TGF-b 对内皮细胞行为的影响取决于培养物中存在的 ECM 成分 [12]。此外，生物物理因素也被认为是内皮细胞行为、间充质细胞分化 [13]、纤维化和骨疾病 [5, 14-24] 的重要决定因素。总而言之，这些先前的研究表明 ECM 衍生的信号可能是 EndMT 的调节因子，进而影响疾病进展。然而，ECM 在指导 EndMT 中的作用在很大程度上是一个尚未探索的研究领域，这可能是由于最近发现这一过程发生在成人组织中。在这里，我们提出了一种识别影响 EndMT 的 ECM 模拟信号的方法。该实验方法基于我们创造材料以有效控制细胞与材料相互作用的经验。该应用的指导性假设是模拟细胞外基质特性的生化和生物物理因素都会显着影响 EndMT 的过程。拟议的研究意义重大，因为它们将为细胞外基质如何促进 EndMT 以及与之相关的疾病提供重要的新见解。已知影响成人组织中 EndMT 的少数因素（例如 BMP-4、TGF-b1、TGF-b2）以及由此导致的内皮细胞表型变化（例如肌成纤维细胞活化、异位成骨）通常与以下因素有关：一系列具有实质性和广泛相关性的疾病。因此，更好地了解 EndMT 的作用可能会对人类健康产生重大益处。拟议的研究具有创新性，因为它们使用新颖的、化学定义的细胞培养阵列来有效探测 ECM 模拟信号的影响。这种探测 ECM 模拟信号的方法对于 EndMT 过程来说是理想的选择，因为 ECM 在 EndMT 中发挥着人们知之甚少但可能至关重要的作用。此外，了解合成生物材料如何影响 EndMT 最终可能与医疗植入物设计相关，特别是在限制纤维化或异位骨化很重要的情况下。