Format

Send to

Choose Destination
Nat Commun. 2019 Jul 5;10(1):2987. doi: 10.1038/s41467-019-10839-0.

Metformin induces lipogenic differentiation in myofibroblasts to reverse lung fibrosis.

Author information

1
Key Laboratory of Interventional Pulmonology of Zhejiang Province, Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, 325035, Wenzhou, China.
2
Cardio-Pulmonary Institute (CPI) and Department of Pulmonary and Critical Care Medicine and Infectious Diseases, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Justus-Liebig University Giessen, 35392, Giessen, Germany.
3
Ludwig Boltzmann Institute for Lung Vascular Research, Otto Loewi Research Center, Medical University Graz, 8010, Graz, Austria.
4
International Collaborative Center on Growth Factor Research and School of Pharmaceutical Sciences, Wenzhou Medical University, 325035, Wenzhou, China.
5
Institut de Pharmacologie Moleculaire et Cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS), UMR 7275, Sophia Antipolis, 06560, Valbonne, France.
6
Universite Cote d'Azur, 06108, Nice, France.
7
Key Laboratory of Interventional Pulmonology of Zhejiang Province, Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, 325035, Wenzhou, China. saverio.bellusci@innere.med.uni-giessen.de.
8
Cardio-Pulmonary Institute (CPI) and Department of Pulmonary and Critical Care Medicine and Infectious Diseases, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Justus-Liebig University Giessen, 35392, Giessen, Germany. saverio.bellusci@innere.med.uni-giessen.de.
9
International Collaborative Center on Growth Factor Research and School of Pharmaceutical Sciences, Wenzhou Medical University, 325035, Wenzhou, China. saverio.bellusci@innere.med.uni-giessen.de.
10
Key Laboratory of Interventional Pulmonology of Zhejiang Province, Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, 325035, Wenzhou, China. elie.el-agha@innere.med.uni-giessen.de.
11
Cardio-Pulmonary Institute (CPI) and Department of Pulmonary and Critical Care Medicine and Infectious Diseases, Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Justus-Liebig University Giessen, 35392, Giessen, Germany. elie.el-agha@innere.med.uni-giessen.de.
12
International Collaborative Center on Growth Factor Research and School of Pharmaceutical Sciences, Wenzhou Medical University, 325035, Wenzhou, China. elie.el-agha@innere.med.uni-giessen.de.

Abstract

Idiopathic pulmonary fibrosis (IPF) is a fatal disease in which the intricate alveolar network of the lung is progressively replaced by fibrotic scars. Myofibroblasts are the effector cells that excessively deposit extracellular matrix proteins thus compromising lung structure and function. Emerging literature suggests a correlation between fibrosis and metabolic alterations in IPF. In this study, we show that the first-line antidiabetic drug metformin exerts potent antifibrotic effects in the lung by modulating metabolic pathways, inhibiting TGFβ1 action, suppressing collagen formation, activating PPARγ signaling and inducing lipogenic differentiation in lung fibroblasts derived from IPF patients. Using genetic lineage tracing in a murine model of lung fibrosis, we show that metformin alters the fate of myofibroblasts and accelerates fibrosis resolution by inducing myofibroblast-to-lipofibroblast transdifferentiation. Detailed pathway analysis revealed a two-arm mechanism by which metformin accelerates fibrosis resolution. Our data report an antifibrotic role for metformin in the lung, thus warranting further therapeutic evaluation.

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center