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

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 depo...

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Published in:Cell stem cell 2017-02, Vol.20 (2), p.261-273.e3
Main Authors: El Agha, Elie, Moiseenko, Alena, Kheirollahi, Vahid, De Langhe, Stijn, Crnkovic, Slaven, Kwapiszewska, Grazyna, Szibor, Marten, Kosanovic, Djuro, Schwind, Felix, Schermuly, Ralph T., Henneke, Ingrid, MacKenzie, BreAnne, Quantius, Jennifer, Herold, Susanne, Ntokou, Aglaia, Ahlbrecht, Katrin, Braun, Thomas, Morty, Rory E., Günther, Andreas, Seeger, Werner, Bellusci, Saverio
Format: Article
Language:English
Subjects:
Actins - metabolism
Animals
Disease Progression
Fibroblast Growth Factor 10 - metabolism
Fibroblasts - metabolism
Fibroblasts - pathology
Humans
Idiopathic Pulmonary Fibrosis - metabolism
Idiopathic Pulmonary Fibrosis - pathology
Lipogenesis
Lung - metabolism
Lung - pathology
Mice
Muscle Development
Myocytes, Smooth Muscle - metabolism
Myocytes, Smooth Muscle - pathology
Myofibroblasts - metabolism
Myofibroblasts - pathology
Phenotype
PPAR gamma - metabolism
Signal Transduction
Transforming Growth Factor beta1 - metabolism
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Summary: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. [Display omitted] •Fate mapping was used to investigate the origin and fate of activated myofibroblasts•Lipofibroblasts are precursors for activated myofibroblasts in lung fibrosis•Activated myofibroblasts dedifferentiate to lipofibroblasts after recovery•PPARγ activation inhibits lipofibroblast-to-myofibroblast transdifferentiation 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.
ISSN:1934-5909
1875-9777
DOI:10.1016/j.stem.2016.10.004