Deciphering the Antifibrotic Property of Metformin

Axelle Septembre-Malaterre; Chailas Boina; Audrey Douanier; Philippe Gasque

doi:10.3390/cells11244090

Deciphering the Antifibrotic Property of Metformin

Cells. 2022 Dec 16;11(24):4090. doi: 10.3390/cells11244090.

Authors

Axelle Septembre-Malaterre^{1

2}, Chailas Boina^{1

2}, Audrey Douanier^{1

2}, Philippe Gasque^{1

2}

Affiliations

¹ Unité de Recherche, EPI 'Etudes en Pharmaco-Immunologie', Université de la Réunion, Allée des Topazes, CS11021, 97400 Saint Denis, France.
² Laboratoire D'immunologie Clinique et Expérimentale de la Zone de L'océan Indien (LICE-OI), CHU La Réunion Site Félix Guyon Allée des Topazes, CS11021, 97400 Saint Denis, France.

Abstract

Fibrosis is a chronic progressive and incurable disease leading to organ dysfunction. It is characterized by the accumulation of extracellular matrix proteins produced by mesenchymal stem cells (MSCs) differentiating into myofibroblasts. Given the complexity of its pathophysiology, the search for effective treatments for fibrosis is of paramount importance. Metformin, a structural dimethyl analog of the galegine guanide extracted from the "French Lilac" (Fabaceae Galega officinalis), is the most widely used antidiabetic drug, recently recognized for its antifibrotic effects through ill-characterized mechanisms. The in vitro model of TGF-β1-induced fibrosis in human primary pulmonary mesenchymal stem cells (HPMSCs), identified as CD248+ and CD90+ cells, was used to study the effects of metformin extracts. These effects were tested on the expression of canonical MSC differentiation markers, immune/inflammatory factors and antioxidative stress molecules using qRT-PCR (mRNA, miRNA), immunofluorescence and ELISA experiments. Interestingly, metformin is able to reduce/modulate the expression of different actors involved in fibrosis. Indeed, TGF-β1 effects were markedly attenuated by metformin, as evidenced by reduced expression of three collagen types and Acta2 mRNAs. Furthermore, metformin attenuated the effects of TGF-β1 on the expression of PDGF, VEGF, erythropoietin, calcitonin and profibrotic miRs, possibly by controlling the expression of several key TGF/Smad factors. The expression of four major fibrogenic MMPs was also reduced by metformin treatment. In addition, metformin controlled MSC differentiation into lipofibroblasts and osteoblasts and had the ability to restore redox balance via the Nox4/Nrf2, AMP and Pi3K pathways. Overall, these results show that metformin is a candidate molecule for antifibrotic effect and/or aiming to combat the development of chronic inflammatory diseases worldwide.

Keywords: fibrosis; inflammation; mesenchymal stem cells; metformin; miRs; myofibroblast; oxidative stress; transdifferentiation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antigens, CD / metabolism
Antigens, Neoplasm / metabolism
Fibrosis
Humans
Lung / pathology
Metformin* / pharmacology
Phosphatidylinositol 3-Kinases / metabolism
Transforming Growth Factor beta1* / metabolism

Substances

Transforming Growth Factor beta1
Metformin
Phosphatidylinositol 3-Kinases
CD248 protein, human
Antigens, Neoplasm
Antigens, CD

Grants and funding

This research was funded by the European Union (CPER/FEDER, EPIGEN Project), Grant Number: 20192211-0022768. Cells and reagents were obtained from additional fundings (CPER FEDER VIROPAM Project), Grant Number: GURDTI 2017-1198-0002583.