MicroRNA and Epithelial-Mesenchymal Interactions in Lung Development and Fibrosis

特发性肺纤维化(IPF)是最常见和最致命的间质性肺疾病，病因不明，是一种高度病态的进行性疾病。IPF的发病机制很复杂，很大程度上还不清楚。目前的假说认为，在老化的肺中，对肺上皮细胞的微重复损伤来源不明，导致无效的修复和随后的纤维化形成。肌成纤维细胞(MYF)是主要的最终病理因素，其主要功能是分泌大量细胞外基质成分，从而促进肺组织硬化。这些间充质细胞的细胞来源仍然存在争议，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、循环中的纤维细胞或上皮细胞。研究小组2最近发表的数据表明，在IPF的发病机制中，常驻脂成纤维细胞(LIF)是肌成纤维细胞池中的一个新的贡献者。当成纤维细胞在纤维化形成过程中发生表型的生脂-生肌开关(LIF-to-MYF Switch)时，当肺纤维化消退时，观察到相反的开关(MYF-to-LIF)，支持MYF去分化模型，并提示操纵这种开关可能为IPF患者提供一种新的治疗选择。一旦MYF焦点开始，复杂的上皮-间充质相互作用，包括直接接触和可溶性介质，有助于疾病的进展。目前已有多条涉及肺发育的生物学途径被报道，提示参与上皮/间充质沟通和上皮细胞可塑性的胚胎信号通路在IPF中被异常地重新激活。我们团队最近的证据强调了microRNAs(MiRNAs)在肺间充质发育过程中或在组织损伤的纤维化反应中调节这些信号通路的作用。重要的是，来自团队1和团队3的未发表的数据有力地支持了旨在干扰这些“Fibromir”的策略的抗纤维化潜力。在这个项目中，三个团队将结合他们的专业知识来阐明miR-142(3p对5p)以及miR-199a/214簇在上皮和间质之间的相互作用中所起的作用，以及在纤维化形成和消退过程中成纤维细胞池的可塑性调节中所起的作用。该项目的力量依赖于对条件miRNA KO小鼠肺表型的最先进研究，谱系追踪方法，使用实验和计算机方法相结合的miRNA靶标识别，获得患者样本和经过验证的临床前小鼠/细胞模型，以及包括单细胞转录的基因组学方法。该项目将允许更好地了解与肺纤维化形成和分解相关的基本分子过程，以此作为设计非编码RNA为基础的针对IPF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.