S100A4 Regulation of IPF Mesenchymal Progenitor Cell Fibrogenicity

S100A4 IPF 间充质祖细胞纤维原性的调节

• 批准号: 10371887
• 负责人: CRAIG A HENKE
• 金额: $ 52.3万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10371887
• 关键词: Alveolar; Autocrine Communication; Automobile Driving; Bleomycin; CD44 gene; Cell Cycle; Cell Differentiation process; Cell Nucleus; Cell Proliferation; Cell physiology; Cell surface; Cells; Clinical; Collagen; Complex; Critical Pathways; Cytoplasm; Data; Deposition; Development; Disease; Disease Progression; Extracellular Matrix; Extracellular Space; Fibroblasts; Fibrosis; Human; Hyaluronan; In Vitro; Integrins; Karyopherins; Knowledge; Lesion by Morphology; Link; Location; Lung; Maintenance; Mediating; Mesenchymal; Mesenchymal Stem Cells; Methyltransferase; Modeling; Molecular; Mus; Myofibroblast; Nonmuscle Myosin Type IIA; Nuclear; Pathologic; Pathway interactions; Patient-Focused Outcomes; Patients; Pattern; Pharmacotherapy; Phenotype; Physical shape; Property; Proteins; Publishing; Pulmonary Fibrosis; Regulation; Reporting; Role; S100A4 gene; Sentinel; Signal Pathway; Signal Transduction; Specimen; Structure; Structure of parenchyma of lung; Subgroup; Supporting Cell; TP53 gene; Therapeutic; Work; Xenograft Model; Xenograft procedure; antifibrotic treatment; base; cancer cell; cell motility; design; experimental study; extracellular; fibrotic lung disease; idiopathic pulmonary fibrosis; in vivo; macrophage; member; mouse model; multicatalytic endopeptidase complex; non-muscle myosin; paracrine; recruit; self-renewal; stem cell function; therapeutically effective

PROJECT SUMMARY Despite modest improvement in patient outcomes from recent advances in pharmacotherapy targeting fibrogenic signaling pathways, Idiopathic Pulmonary Fibrosis (IPF) remains a major unsolved clinical problem. One reason for this is that currently available anti-fibrotic agents slow but do not arrest fibrotic progression. To fully arrest fibrotic progression, its obligatory drivers need to be identified. We have made several recent discoveries studying primary cells and ECM from IPF patients that illuminate a path forward toward understanding mechanisms driving the relentless progression of fibrosis following disease initiation. We learned that fibrosis progression involves cell-intrinsic/autonomous mechanisms. Cell-autonomous fibrogenicity was established by our discovery of fibrogenic mesenchymal progenitor cells (MPCs) in the lungs of patients with IPF and that S100A4 mediates their fibrogenicity. Our data indicate that fibrogenic mesenchymal cells residing in a fibrogenic ECM is a key driver of fibrotic progression in the human IPF lung. We have recently discovered that the sentinel morphologic lesion of IPF, the fibroblastic focus, is a polarized structure with an active fibrotic front that contains IPF MPCs, their transit amplifying progeny and activated macrophages residing in a hyaluronan (HA)-rich extracellular matrix (ECM) that supports their pathological properties. In contrast, the core of the fibroblastic focus is a collagen-rich region containing non-cycling myofibroblasts actively synthesizing and depositing ECM. In this proposal we will: i) examine the role of nuclear, cytoplasmic and extracellular S100A4 in regulating the fibrogenicity of IPF MPCs and their progeny; ii) define the key components of the fibrogenic niche microenvironment that regulate S100A4 function; and iii) identify subgroups of phenotypically distinct MPCs within the fibrogenic niche that cooperate to drive fibrotic progression. Two Aims are proposed: In Aim 1 we will determine the molecular mechanism by which the HA-CD44 axis regulates nuclear S100A4 function and MPC self-renewal and identify subgroups of IPF MPCs based on SSE4 and HA cell surface expression; in Aim 2 we will determine the role of cytoplasmic S100A4 in acquisition of a motile phenotype as IPF MPCs differentiate to IPF fibroblasts; and examine the role of IPF MPC progeny-derived extracellular S100A4 in driving fibrotic progression. New knowledge about subgroups of fibrogenic MPCs, the cells that support them within the active fibrotic front, and fibrogenic signals in the microenvironment; has the potential to greatly advance the design of therapeutics that fully arrest fibrotic progression and even reverse established fibrosis. !

项目总结 尽管靶向药物治疗的最新进展使患者的预后略有改善 随着纤维化信号转导途径的研究，特发性肺纤维化(IPF)仍是临床上尚未解决的主要问题。 其中一个原因是，目前可用的抗纤维化药物减缓但不能阻止纤维化进展。至 要完全遏制纤维化进展，就需要确定其必备驱动因素。我们最近做了几件事 对IPF患者原代细胞和ECM的研究发现照亮了前进的道路 了解疾病开始后导致纤维化持续发展的机制。我们 了解到纤维化进展涉及细胞固有/自主机制。细胞自主性致纤维化 是由我们在患者肺中发现的纤维化间充质祖细胞(MPC)建立的 IPF和S100A4介导了它们的纤维化。我们的数据表明，纤维性间充质细胞 居住在纤维化的ECM中是人IPF肺纤维化进展的关键驱动因素。我们最近做了 发现成纤维细胞病灶IPF的前哨形态病变是一种极化结构，具有 含有IPF间质祖细胞、它们的转运扩增后代和活化的巨噬细胞的活动性纤维化前沿 存在于富含透明质酸(HA)的细胞外基质(ECM)中，支持其病理特性。在……里面 相反，成纤维细胞病灶的核心是一个富含胶原的区域，包含非循环性肌成纤维细胞。 积极合成和沉积ECM。在这项建议中，我们将：i)研究核、细胞质 和细胞外S100A4在调节IPF MPC及其后代成纤维活性中的作用；ii)定义关键 调节S100A4功能的致纤维化生态位微环境的成分；以及iii)识别亚群 在纤维形成的小生境中，表型不同的MPC协同推动纤维化进展。二 提出目标：在目标1中，我们将确定HA-CD44轴调节的分子机制 核S100A4功能与MPC自我更新及基于SSE4和HA的IPF MPC亚群鉴定 在目标2中，我们将确定细胞质S100A4在获得运动性 IPF-MPC向IPF成纤维细胞分化的表型；并检测IPF-MPC后代来源的作用 细胞外S100A4在推动纤维化进展中的作用关于纤维化MPC亚群的新认识 在活跃的纤维化前沿支持它们的细胞，以及微环境中的纤维化信号；具有 有可能极大地推进完全阻止纤维化进展甚至逆转的治疗方法的设计 已确诊的纤维化症。 好了！