Molecular Bases of Activated Myofibroblast (MYF) to Lipofibroblast (LIF) Phenotype switching during Fibrosis Resolution.

• Applicant: Professor Dr. Saverio Bellusci
• Subject Area: Pneumology, Thoracic Surgery ; Developmental Biology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 435231213

Idiopathic pulmonary fibrosis (IPF) is a form of interstitial lung disease with unknown etiology. Due to its progressive nature and lack of effective treatment, IPF is associated with a high mortality rate. The hallmark feature of this disease is the accumulation of activated myofibroblasts that excessively deposit extracellular matrix proteins, thus compromising lung architecture and function, and hindering gas exchange. Therefore, understanding the cellular origin of activated myofibroblasts and the molecular mechanisms governing fibrosis formation and resolution is an urgent clinical need. During the first funding period, multiple transgenic and knock-in mouse lines were used to label lipogenic or myogenic populations of lung fibroblasts in a time-controlled manner, and monitor them during fibrosis formation and resolution. Our published data demonstrate a lipogenic-to-myogenic switch in fibroblast phenotype during fibrosis formation. We identify the resident lipofibroblast as a novel contributor to the myofibroblast pool in the pathogenesis of IPF. Conversely during fibrosis resolution, a myogenic-to-lipogenic switch was observed in the lungs of these mice supporting the myofibroblast dedifferentiation model. Analysis of human lung tissues and functional analysis of primary human lung fibroblasts revealed that this mechanism is involved in the pathogenesis of IPF, suggesting that manipulating this switch might offer a novel therapeutic option for IPF patients. In this DFG project, we will use the bleomycin model to induce fibrosis formation in young and aged mice to investigate, using an in vivo lineage-tracing approach and single cell RNA sequencing, the cellular and transcriptomic characteristics of the activated myofibroblasts in the "fibrotic lesions" and their fate during normal (in young mice) and impaired (in aged mice) fibrosis resolution. Our goal is to define trajectories of differentiation for the activated MYF during the resolution process. These results will be instrumental in enhancing fibrosis resolution in IPF.

• DFG Programme: Research Grants