MicroRNA and Epithelial-Mesenchymal Interactions in Lung Development and Fibrosis

特发性肺纤维化（IPF）是一种病因不明的最常见和致死性间质性肺病，是一种高度病态的进行性疾病。IPF的发病机制很复杂，而且在很大程度上尚不清楚。目前的假说表明，在老化的肺中，不明原因的肺上皮细胞的微重复损伤导致无效的修复，随后发生纤维化。肌成纤维细胞（MYF）作为主要的最终病理因素出现，特别是通过分泌大量的细胞外基质成分，从而促进肺组织硬化。这些间充质细胞的细胞起源仍有争议，过去十年的研究证据表明，不同的细胞来源包括局部间质成纤维细胞池、周细胞、循环纤维细胞或上皮细胞。研究小组2最近发表的数据已将常驻脂肪成纤维细胞（LIF）确定为IPF发病机制中肌成纤维细胞池的新贡献者。虽然在纤维化形成期间成纤维细胞中发生表型脂肪生成至肌生成转换（LIF至MYF转换），但当肺纤维化消退时观察到相反的转换（MYF至LIF），支持MYF去分化模型，并表明操纵该转换可能为IPF患者提供新的治疗选择。一旦启动MYF焦点，复杂的上皮-间充质相互作用，包括直接接触和可溶性介质有助于疾病进展。多个生物学途径，往往参与肺发育已被报道，这表明，胚胎信号通路参与上皮/间充质通信和上皮细胞可塑性异常重新激活在IPF。最近的证据，从我们的团队强调了发挥作用的microRNAs（miRNAs）在调节这些信号通路在肺间充质在发育过程中或在纤维化反应组织损伤。重要的是，来自团队1和3的未发表数据强烈支持旨在干扰这些“FibromiR”的策略的抗纤维化潜力。在这个项目中，3个团队将汇集他们的专业知识，阐明miR-142（3p vs. 5p）以及miR-199a/214簇在上皮和间充质之间的相互作用中以及在纤维化形成和解决过程中调节成纤维细胞池的可塑性中所发挥的作用。该项目的优势依赖于对条件性miRNA KO小鼠肺表型的最新研究、谱系追踪方法、使用实验和计算机模拟方法相结合的miRNA靶点鉴定，获得患者样本和经验证的临床前小鼠/细胞模型以及基因组学方法，包括单-该项目将允许更好地理解与肺纤维化形成和消退相关的基本分子过程，作为设计针对IPF的基于非编码RNA的创新疗法的一种方式。

Idiopathic Pulmonary Fibrosis (IPF), the most common and lethal interstitial lung disease of unknown etiology, is a highly morbid progressive disorder. The pathogenesis of IPF is complex and largely unknown. Current hypotheses suggest that microrepetitive injury of unknown origin to pulmonary epithelial cells in the aging lung results in ineffective repair with subsequent fibrogenesis. Myofibroblasts (MYFs) appear as the main final pathological actor, notably by secreting important amount of Extracellular Matrix components thus promoting lung tissue stiffening. The cellular origin of these mesenchymal cells is still debated and evidence from studies during the last decade suggest distinct cellular sources including local interstitial fibroblast pools, pericytes, circulating fibrocytes or epithelial cells. Recent published data from Team 2 have identified the resident lipofibroblast (LIFs) as a novel contributor to the myofibroblast pool in the pathogenesis of IPF. While a phenotypic lipogenic-to-myogenic switch occurs in fibroblast (LIF-to-MYF switch) during fibrosis formation, an opposite switch (MYF-to-LIF) was observed when lung fibrosis resolved, supporting the MYF dedifferentiation model and suggesting that manipulating this switch might offer a novel therapeutic option for IPF patients. Once the MYF focus is initiated, complex epithelial–mesenchymal interactions including direct contacts and soluble mediators contribute to disease progression. Multiple biological pathways, often involved in lung development have been reported, suggesting that embryonic signaling pathways involved in epithelium/ mesenchymal communication and epithelial cell plasticity are aberrantly reactivated in IPF.Recent evidence from our teams has emphasized the roles played by microRNAs (miRNAs) in regulating these signaling pathways in lung mesenchyme during development or during the fibrogenic response to tissue injury. Importantly, unpublished data from Teams 1 and 3 strongly support the anti-fibrotic potential of strategies aiming at interfering with these “FibromiRs”. In this project, the 3 teams will bring together their expertise to elucidate the role played by miR-142 (3p vs. 5p) as well as the miR-199a/214 cluster in the interaction between epithelium and mesenchyme and in the regulation of the plasticity of fibroblast pools during fibrosis formation and resolution. The strength of the project relies on the state-of the art investigation of lung phenotype in conditional miRNA KO mice, lineage tracing approaches, miRNA target identification using a combination of experimental and in silico approaches, access to patient samples and validated preclinical mouse / cell models as well as genomics approaches including single-cell transcriptomics.This project will allow a better understanding of the basic molecular processes associated with lung fibrosis formation and resolution as a way to design non-coding RNA- based innovative therapies against IPF.