Metformin induces lipogenic differentiation in myofibroblasts to reverse lung fibrosis

Vahid Kheirollahi,Bernard Mari,Valentina Biasin,Susanne Herold,Alena Moiseenko,Jochen Wilhelm,Saverio Bellusci,Werner Seeger,Ralph T Schermuly,Xuran Chu,Ana Ivonne Vazquez-Armendariz,Roxana M Wasnick,Elie El Agha,Xiaokun Li,Grazyna Kwapiszewska,Astrid Weiss,Andreas Günther,Jin-San Zhang

doi:10.1038/s41467-019-10839-0

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.

Highlights

Idiopathic pulmonary fibrosis (IPF) is a fatal disease in which the intricate alveolar network of the lung is progressively replaced by fibrotic scars
We found that myofibroblasts retain their plasticity and are able to revert to the type 2 alveolar epithelial cell (AT2)-supportive lipofibroblast fate during recovery[8]
In order to investigate whether metformin impacts lipogenic versus myogenic fibroblastic phenotypes in the lung, we carried out a dose-finding study

Summary

Introduction

Idiopathic pulmonary fibrosis (IPF) is a fatal disease in which the intricate alveolar network of the lung is progressively replaced by fibrotic scars. Histopathological examination of IPF lungs typically reveals extensive alveolar scarring; i.e., replacement of normal alveoli by fibrous scars containing myofibroblasts The latter cells are considered to be the main source of excessive extracellular matrix (ECM) protein deposition, collagen[2], in IPF lungs and in fibrosis of other organs. The paradigm is that identifying the precursor cell of the myofibroblast might pave the way for preventive and/or therapeutic, selective intervention in IPF patients In this context, it is suggested that the myofibroblast pool is heterogeneous, and derives from multiple sources such as resident fibroblasts, circulating fibrocytes, perivascular mesenchymal cells, and alveolar epithelial cells[4,5,6,7]. A recent report has shown that IPF lungs display alterations in several metabolites linked to energy consumption[14]

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Results

Conclusion