Myofibroblasts in pulmonary fibrosis: origin, clones and KLF4

肺纤维化中的肌成纤维细胞：起源、克隆和 KLF4

• 批准号: 9124490
• 负责人: Rachana Radhamani Chandran
• 金额: $ 5.43万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9124490
• 关键词: Adult; Affect; Alveolar; Architecture; Attenuated; Beta Cell; Biology; Birth; Bleomycin; Cells; Cessation of life; Development; Disease; Distal; Extracellular Matrix; Fibrosis; GKLF protein; Genes; Genetic; Goals; Hamman-Rich syndrome; Health; Heart; Human; Hypoxia; Interstitial Lung Diseases; Investigation; Knockout Mice; Lung; Mus; Myofibroblast; Organ; Pathogenesis; Patients; Pattern; Pericytes; Platelet-Derived Growth Factor beta Receptor; Play; Process; Pulmonary Fibrosis; Pulmonary Hypertension; Role; Sampling; Seminal; Smooth Muscle; Smooth Muscle Myocytes; Source; Structure of parenchyma of lung; Technology; Testing; Therapeutic; Tissues; Translating; United States; Up-Regulation; arteriole; cell dedifferentiation; cell type; design; indium-bleomycin; insight; interstitial cell; lung development; lung hypoxia; lung injury; lung maturation; mouse model; novel; novel therapeutics; outcome forecast; pluripotency; postnatal; prevent; progenitor

DESCRIPTION (provided by applicant): Idiopathic pulmonary fibrosis (IPF) is the most common interstitial lung disease and has a dismal prognosis with a median survival of 2-3 years. IPF treatments are limited as the pathogenesis is not well delineated. Alveolar myofibroblasts are implicated as major producers of fibrotic tissue in disease, yet their biology i poorly understood. Interestingly, myofibroblasts are key players in postnatal alveologenesis and subsequently decrease in number until they are essentially absent in the adult. Yet, alveolar myofibroblasts re-accumulate in human IPF and in the widely used bleomycin-induced murine model of lung fibrosis. In addition, these cells are present in human pulmonary hypertension, and hypoxia, which often complicates IPF, induces myofibroblast accumulation and pulmonary hypertension. The cellular origin(s) of pathological alveolar myofibroblasts is not well defined, and the clonal architecture of myofibroblasts in any organ and in any setting (i.e., development or disease) have not been studied. As has been critical in our studies of other processes, herein, we will use cell-specific CreER-loxP technology to identify the progenitors of pathological myofibroblasts and state-of-the-art clonal analysis to assess the clonal relationship of myofibroblasts. Pluripotency factors induce cell dedifferentiation and reprogramming, and we propose that one such factor KLF4 plays a key role in the conversion of lung cell types to myofibroblasts in lung fibrosis. We demonstrate that KLF4 is upregulated in alveolar myofibroblasts and pericytes in the fibrotic lung of humans with IPF and mice treated with bleomycin. Remarkably, our initial studies also indicate that deletion of Klf4 in PDGFR-β+ cells completely prevents hypoxia-induced accumulation of alveolar myofibroblasts. Herein, we focus on lung fibrosis, and our main goal is to generate key insights into alveolar myofibroblast biology that can be translated into therapies for human IPF. To this end, we use genetic, clonal and histochemical analysis to study alveolar myofibroblasts in human IPF samples and mouse models of lung injury. We hypothesize KLF4 plays a crucial role in the conversion of lung cell types into alveolar myofibroblasts in lung fibrosis and test this hypothesis with two specific aims 1) determine the origin and clonal relationship of alveolar myofibroblasts in bleomycin-induced pulmonary fibrosis; and 2) elucidate the role of pluripotency factor KLF4 in alveolar myofibroblast accumulation and lung fibrosis.

特发性肺纤维化（IPF）是最常见的间质性肺病，预后差，中位生存期为2-3年。由于发病机制尚未明确，IPF治疗受到限制。肺泡肌成纤维细胞是疾病中纤维化组织的主要生产者，但对其生物学知之甚少。有趣的是，肌成纤维细胞是出生后肺泡发生的关键参与者，随后数量减少，直到成年后基本上不存在。然而，肺泡肌成纤维细胞在人IPF和广泛使用的博来霉素诱导的肺纤维化小鼠模型中重新积聚。此外，这些细胞存在于人肺动脉高压和缺氧中，缺氧通常使IPF复杂化，诱导肌成纤维细胞积聚和肺动脉高压。病理性肺泡肌成纤维细胞的细胞起源没有很好地定义，并且肌成纤维细胞在任何器官和任何环境中的克隆结构（即，疾病或疾病）尚未研究。正如我们对其他过程的研究中至关重要的那样，在本文中，我们将使用细胞特异性CreER-loXP技术来鉴定病理性细胞的祖细胞 肌成纤维细胞和最先进的克隆分析，以评估肌成纤维细胞的克隆关系。 多能性因子诱导细胞去分化和重编程，我们提出这样一种因子KLF 4在肺纤维化中肺细胞类型向肌成纤维细胞的转化中起关键作用。我们证明，KLF 4在患有IPF的人类和用博来霉素治疗的小鼠的纤维化肺中的肺泡肌成纤维细胞和周细胞中上调。值得注意的是，我们的初步研究还表明，PDGFR-β+细胞中Klf 4的缺失完全阻止了缺氧诱导的肺泡肌成纤维细胞的积累。在此，我们专注于肺纤维化，我们的主要目标是产生对肺泡肌成纤维细胞生物学的关键见解 可以转化为人类IPF的治疗方法。为此，我们使用遗传、克隆和组织化学分析来研究人IPF样本和肺损伤小鼠模型中的肺泡肌成纤维细胞。我们假设KLF 4在肺纤维化中肺细胞类型转化为肺泡肌成纤维细胞中起关键作用，并以两个特定目的测试该假设：1）确定博莱霉素诱导的肺纤维化中肺泡肌成纤维细胞的起源和克隆关系; 2）阐明多能性因子KLF 4在肺泡肌成纤维细胞积聚和肺纤维化中的作用。