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. !

项目摘要 尽管药物治疗靶向的最新进展使患者结局略有改善， 在纤维化信号传导途径中，特发性肺纤维化（IPF）仍然是未解决的主要临床问题。 其原因之一是目前可用的抗纤维化剂减缓但不阻止纤维化进展。到 为了完全阻止纤维化进展，需要确定其强制性驱动因素。我们最近做了几个 研究IPF患者的原代细胞和ECM的发现， 了解疾病开始后纤维化无情进展的机制。我们 了解到纤维化进展涉及细胞内在/自主机制。细胞自主性纤维化 是通过我们在患者肺中发现纤维化间充质祖细胞（MPC）而建立的 S100 A4介导了IPF的纤维化。我们的数据表明，纤维化间充质细胞 存在于纤维化ECM中是人IPF肺纤维化进展的关键驱动因素。我们最近 发现特发性肺纤维化的前哨形态学病变（成纤维细胞病灶）是一种极化结构，具有 含有IPF MPC、其转运扩增子代和活化巨噬细胞的活性纤维化前沿 存在于支持其病理性质的富含透明质酸（HA）的细胞外基质（ECM）中。在 相反，成纤维细胞病灶的核心是富含胶原的区域，包含非循环肌成纤维细胞 活性合成和沉积ECM。在这项建议中，我们将：i）检查核，细胞质和细胞质的作用， 和细胞外S100 A4在调节IPF MPC及其后代的纤维化中的作用; ii）确定关键 调节S100 A4功能的纤维化小生境微环境的组分;和iii）鉴定亚组 表型不同的MPC在纤维化生态位内协同驱动纤维化进展。两 提出的目的：在目的1中，我们将确定HA-CD 44轴调节的分子机制。 核S100 A4功能和MPC自我更新，并基于SSE 4和HA鉴定IPF MPC亚组 细胞表面表达;在目标2中，我们将确定细胞质S100 A4在获得运动细胞中的作用。 表型作为IPF MPC分化成IPF成纤维细胞;并检查IPF MPC祖细胞衍生的 细胞外S100 A4驱动纤维化进展。关于纤维化MPC亚群的新知识， 在活跃的纤维化前沿内支持它们的细胞，以及微环境中的纤维化信号; 有可能大大推进完全阻止纤维化进展甚至逆转纤维化的治疗方法的设计。 形成纤维化。 !