Pericyte reprogramming in fibrosis

纤维化中的周细胞重编程

• 批准号: 10578526
• 负责人: Anjelica Gonzalez
• 金额: $ 48.73万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10578526
• 关键词: 3-Dimensional; Actins; Acute; Adopted; Adoption; Affect; Animal Model; Area; Automobile Driving; Biochemical; Biocompatible Materials; Biological Assay; Biology; Biomedical Engineering; Blood Vessels; Blood capillaries; Cell Adhesion Molecules; Cells; Chemicals; Chronic; Clinical; Deposition; Development; Diagnosis; Disease; Dropout; Endothelium; Epithelial Cells; Event; Exposure to; Extracellular Matrix; Extracellular Matrix Proteins; Fibrosis; Functional disorder; Growth; Growth Factor; Health; Heart; Homeostasis; Human; In Situ; Individual; Inflammation; Inflammatory; Influentials; Integrins; Interstitial Lung Diseases; Intervention; Investigation; Kidney; Knowledge; Lesion; Liver; Lung; MCAM gene; Maintenance; Mechanics; Mediating; Mediator; Metabolic; Methods; Microvascular Dysfunction; Mitochondria; Molecular; Molecular Biology; Monitor; Myofibroblast; Organ; Pathologic; Pathway interactions; Patients; Pericytes; Permeability; Phenotype; Polymers; Population; Process; Profibrotic signal; Publishing; Pulmonary Fibrosis; RNA marker; Regulation; Role; Sampling; Severity of illness; Signal Transduction; Skin; Smooth Muscle; Source; Staging System; Structure; Technology; Therapeutic; Therapeutic Intervention; Time; Tissues; Transforming Growth Factor beta; Transforming Growth Factors; Translating; Vascular remodeling; Work; cell type; clinically relevant; design; disease diagnosis; experience; in vitro Model; interstitial; mechanical signal; mouse model; necrotic tissue; prevent; programs; protein biomarkers; response; stem; stem cell biomarkers; stem cells; stem-like cell; therapeutically effective; transcriptome sequencing; vascular contributions; vascular injury

Prior to clinical evidence of fibrosis, microvascular injury occurs, presenting as an altered functional state of the endothelium, increased permeability, enhanced vasoreactivity, increased expression of adhesion molecules, excessive inflammation, and altered vascular wall growth. Microvascular rarefaction, or capillary dropout, is coincident with chronic fibrosis, and considered an accelerator of the disease. However little is known about the microvascular contribution to fibrotic diseases in which microvasculature are key to tissue health and homeostasis. Given the central role of the vasculature in barrier function, inflammatory regulation and interstitial tissue necrosis, it is likely that the microvasculature, specifically, mural perivascular cells (pericytes), are key contributors to fibrotic development and progression. Recent evidence suggests that microvascular dysfunction may be more directly influential to tissue remodeling than epithelial cells. Limited availability of human pericytes from a readily available human source has led to an incomplete understanding of the mechanisms underlying pericyte to myofibroblast transition that facilitate both microvascular and interstitial matrix remodeling. Our work, supported by that of others in this area, has led us to the hypothesis that pericytes cease homeostatic maintenance of the microvasculature by transition into a myofibroblast through the process of dedifferentiation and re-differentiation known as cellular reprogramming. As myofibroblasts, cells of pericyte lineage contribute to interstitial tissue fibrosis. Through three distinct aims we will show that, in response to growth factor, pericytes deposit extracellular matrix proteins to alternatively support vascular stability and fibrosis as they undergo phenotypic transition from microvascular pericytes to interstitial myofibroblasts. We also determine points in pericyte transition that may be key for therapeutic intervention. We utilize traditional molecular biology methods and biomaterials technology to determine the profibrotic mediators promote functional and phenotypic shifts in pericytes. Using 2- and 3-D bioengineered mechanically and biochemically tunable polymer based extracellular matrices, we decouple the role of biochemical and mechanical signals in regulation of PC to myofibroblast transition through the process of reprogramming. Results acquired through use of human cells in bioengineered structures will be validated with animal models of pulmonary fibrosis.

在临床证据的纤维化证据之前，发生微血管损伤，作为改变的功能状态 内皮，渗透率增加，血管反应性增强，粘附分子的表达增加， 过度炎症，并改变了血管壁的生长。微血管稀疏或毛细血管辍学是 与慢性纤维化一致，并被认为是该疾病的促进剂。但是，关于 微血管对微血管疾病是组织健康的关键和的纤维性疾病的贡献 稳态。鉴于脉管系统在屏障功能中的核心作用，炎症调节和间隙 组织坏死很可能是壁血管系统，具体是壁血管周围细胞（周细胞），是关键 纤维化发育和进展的贡献者。最近的证据表明微血管功能障碍 与上皮细胞相比，对组织重塑的影响可能更直接。人周围的可用性有限 从易于使用的人类来源导致对基本机制的不完全理解 周围向肌纤维细胞过渡，可促进微血管和间质基质重塑。我们的工作， 在该领域的其他人的支持下，我们提出了一个假设，即周细胞停止体内平衡 通过过渡到肌纤维细胞的过程中维护微脉管系统 去分化和重新分化称为细胞重编程。作为肌纤维细胞， 周细胞谱系有助于间质组织纤维化。通过三个不同的目标，我们将表明， 对生长因子的反应，周细胞沉积细胞外基质蛋白以支持血管稳定性 和纤维化，因为它们经历了从微血管周细胞到间质肌纤维细胞的表型过渡。我们 还确定周细胞过渡的点可能是治疗干预的关键。我们利用传统 分子生物学方法和生物材料技术来确定纤维化介质促进 周细胞的功能和表型转移。使用2和3-D生物工程进行机械和生化的生化 基于可调聚合物的细胞外矩阵，我们将生化和机械信号在 通过重新编程的过程调节PC向肌纤维细胞过渡。通过使用获得的结果 生物工程结构中的人类细胞将通过肺纤维化的动物模型来验证。