FIBROMIR

Idiopathic Pulmonary Fibrosis (IPF), the most common and lethal interstitial lung disease of unknown etiology, is a highly morbid progressive disorder. IPF is a disease associated with aging and as such its incidence is anticipated to gradually increase as the proportion of the population of older adults increases. Lung fibrosis is an irreversible phenomenon and, despite two recent trials showing significant reductions in the rate of decline in lung function in patients treated with two new antifibrotic drugs there is no current therapy improving survival other than lung transplantation. 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, epithelial or endothelial 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, including Wnt, Notch, hedgehog, PDGF, FGF and TGF-beta, 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 (several publications from the 3 teams and one patent from Teams 1 & 3). 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. Overall the FibromiR 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.