title: Two-Way Conversion between Lipogenic and Myogenic Fibroblastic Phenotypes Marks the Progression and Resolution of Lung Fibrosis.
abstract: 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.
authors.affiliation: Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, member of the German Center for Lung Research, Justus-Liebig-University Giessen, 35392 Giessen, Germany.
authors.forename: Elie
authors.initials: E
authors.lastname: El Agha
authors.affiliation: Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, member of the German Center for Lung Research, Justus-Liebig-University Giessen, 35392 Giessen, Germany.
authors.forename: Alena
authors.initials: A
authors.lastname: Moiseenko
authors.affiliation: Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, member of the German Center for Lung Research, Justus-Liebig-University Giessen, 35392 Giessen, Germany.
authors.forename: Vahid
authors.initials: V
authors.lastname: Kheirollahi
authors.affiliation: Department of Pediatrics, Division of Cell Biology, National Jewish Health, Denver, CO 80206, USA.
authors.forename: Stijn
authors.initials: S
authors.lastname: De Langhe
authors.affiliation: Ludwig Boltzmann Institute for Lung Vascular Research, Center for Medical Research, 8010 Graz, Austria.
authors.forename: Slaven
authors.initials: S
authors.lastname: Crnkovic
authors.affiliation: Ludwig Boltzmann Institute for Lung Vascular Research, Center for Medical Research, 8010 Graz, Austria.
authors.forename: Grazyna
authors.initials: G
authors.lastname: Kwapiszewska
authors.affiliation: Institute of Biotechnology, FinMIT Cluster of Excellence, Viikinkaari 5, FI-00790 Helsinki, Finland.
authors.forename: Marten
authors.initials: M
authors.lastname: Szibor
authors.affiliation: Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, member of the German Center for Lung Research, Justus-Liebig-University Giessen, 35392 Giessen, Germany.
authors.forename: Djuro
authors.initials: D
authors.lastname: Kosanovic
authors.affiliation: Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, member of the German Center for Lung Research, Justus-Liebig-University Giessen, 35392 Giessen, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Schwind
authors.affiliation: Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, member of the German Center for Lung Research, Justus-Liebig-University Giessen, 35392 Giessen, Germany.
authors.forename: Ralph T
authors.initials: RT
authors.lastname: Schermuly
authors.affiliation: Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, member of the German Center for Lung Research, Justus-Liebig-University Giessen, 35392 Giessen, Germany.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Henneke
authors.affiliation: Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, member of the German Center for Lung Research, Justus-Liebig-University Giessen, 35392 Giessen, Germany.
authors.forename: BreAnne
authors.initials: B
authors.lastname: MacKenzie
authors.affiliation: Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, member of the German Center for Lung Research, Justus-Liebig-University Giessen, 35392 Giessen, Germany.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Quantius
authors.affiliation: Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, member of the German Center for Lung Research, Justus-Liebig-University Giessen, 35392 Giessen, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Herold
authors.affiliation: Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, member of the German Center for Lung Research, Justus-Liebig-University Giessen, 35392 Giessen, Germany; Max Planck Institute for Heart and Lung Research, W.G. Kerckhoff Institute, 61231 Bad Nauheim, Germany.
authors.forename: Aglaia
authors.initials: A
authors.lastname: Ntokou
authors.affiliation: Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, member of the German Center for Lung Research, Justus-Liebig-University Giessen, 35392 Giessen, Germany; Max Planck Institute for Heart and Lung Research, W.G. Kerckhoff Institute, 61231 Bad Nauheim, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Ahlbrecht
authors.affiliation: Max Planck Institute for Heart and Lung Research, W.G. Kerckhoff Institute, 61231 Bad Nauheim, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Braun
authors.affiliation: Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, member of the German Center for Lung Research, Justus-Liebig-University Giessen, 35392 Giessen, Germany; Max Planck Institute for Heart and Lung Research, W.G. Kerckhoff Institute, 61231 Bad Nauheim, Germany.
authors.forename: Rory E
authors.initials: RE
authors.lastname: Morty
authors.affiliation: Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, member of the German Center for Lung Research, Justus-Liebig-University Giessen, 35392 Giessen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Günther
authors.affiliation: Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, member of the German Center for Lung Research, Justus-Liebig-University Giessen, 35392 Giessen, Germany; Max Planck Institute for Heart and Lung Research, W.G. Kerckhoff Institute, 61231 Bad Nauheim, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.affiliation: Excellence Cluster Cardio-Pulmonary System, Universities of Giessen and Marburg Lung Center, member of the German Center for Lung Research, Justus-Liebig-University Giessen, 35392 Giessen, Germany; College of Life and Environmental Sciences, Wenzhou University, Wenzhou, Zhejiang, China. Electronic address: saverio.bellusci@innere.med.uni-giessen.de.
authors.forename: Saverio
authors.initials: S
authors.lastname: Bellusci
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D018450:Disease Progression; D051526:Fibroblast Growth Factor 10 / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000378:metabolism / Q000473:pathology*; D050155:Lipogenesis; D008168:Lung / Q000378:metabolism / Q000473:pathology; D051379:Mice; D024510:Muscle Development; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology; D047495:PPAR gamma / Q000378:metabolism; D010641:Phenotype; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: C558396:Acta2 protein, mouse; D000199:Actins; D051526:Fibroblast Growth Factor 10; D047495:PPAR gamma; D053773:Transforming Growth Factor beta1