MicroRNA and Epithelial-Mesenchymal Interactions in Lung Development and Fibrosis

• Applicant: Professor Dr. Saverio Bellusci
• Subject Area: Developmental Biology
• Term: from 2018 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 406538808

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 Importantly, unpublished data from Teams 1 and 3 strongly support the anti-fibrotic potential of strategies aiming at interfering with these “FibromiRs”.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.

• DFG Programme: Research Grants
• International Connection: France
• Partner Organisation: Agence Nationale de la Recherche / The French National Research Agency
• Cooperation Partners: Bernard Mari, Ph.D.; Dr. Nicolas Pottier