Two-Way Conversion between Lipogenic and Myogenic Fibroblastic Phenotypes Marks the Progression and Resolution of Lung Fibrosis

Publication date: Available online 17 November 2016
Source:Cell Stem Cell
Author(s): Elie El Agha, Alena Moiseenko, Vahid Kheirollahi, Stijn De Langhe, Slaven Crnkovic, Grazyna Kwapiszewska, Djuro Kosanovic, Felix Schwind, Ralph T. Schermuly, Ingrid Henneke, BreAnne MacKenzie, Jennifer Quantius, Susanne Herold, Aglaia Ntokou, Katrin Ahlbrecht, Rory E. Morty, Andreas Günther, Werner Seeger, Saverio Bellusci
Idiopathic pulmonary fibrosis (IPF) is a form of progressive interstitial lung disease with unknown etiology. Due to a 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. Here we investigated the origin of activated myofibroblasts and the molecular mechanisms governing fibrosis formation and resolution. Genetic engineering in mice enables the time-controlled labeling and monitoring of lipogenic or myogenic populations of lung fibroblasts during fibrosis formation and resolution. Our data demonstrate a lipogenic-to-myogenic switch in fibroblastic phenotype during fibrosis formation. Conversely, we observed a myogenic-to-lipogenic switch during fibrosis resolution. Analysis of human lung tissues and primary human lung fibroblasts indicates that this fate switching is involved in IPF pathogenesis, opening potential therapeutic avenues to treat patients.

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Teaser

El Agha et al. use genetic engineering in mice to identify precursor cells for activated myofibroblasts and investigate their fate in a reversible model of lung fibrosis. Their findings emphasize the phenotypic plasticity of lipogenic and myogenic lung fibroblasts and indicate that PPARγ agonists might be beneficial in treating IPF.


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