Deciphering the Antifibrotic Property of Metformin

Overview

Journal Cells

Publisher MDPI

Specialties Biochemistry
Biophysics
Cell Biology
Molecular Biology

Date 2022 Dec 23

PMID 36552855

Authors

Axelle Septembre-Malaterre

Chailas Boina

Audrey Douanier

Philippe Gasque

Affiliations

Soon will be listed here.

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 ), 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.

References

Henry T, Mendoza F, Jimenez S . Role of microRNA in the pathogenesis of systemic sclerosis tissue fibrosis and vasculopathy. Autoimmun Rev. 2019; 18(11):102396. DOI: 10.1016/j.autrev.2019.102396. View

Crunkhorn S . miR-21 antagomir reverses COPD pathology. Nat Rev Drug Discov. 2021; 21(1):20. DOI: 10.1038/d41573-021-00199-0. View

Mosmann T . Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983; 65(1-2):55-63. DOI: 10.1016/0022-1759(83)90303-4. View

Duffield J, Lupher M, Thannickal V, Wynn T . Host responses in tissue repair and fibrosis. Annu Rev Pathol. 2012; 8:241-76. PMC: 3789589. DOI: 10.1146/annurev-pathol-020712-163930. View

Wolters P, Collard H, Jones K . Pathogenesis of idiopathic pulmonary fibrosis. Annu Rev Pathol. 2013; 9:157-79. PMC: 4116429. DOI: 10.1146/annurev-pathol-012513-104706. View

Noble P, Albera C, Bradford W, Costabel U, Glassberg M, Kardatzke D . Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet. 2011; 377(9779):1760-9. DOI: 10.1016/S0140-6736(11)60405-4. View

Yamashita C, Dolgonos L, Zemans R, Young S, Robertson J, Briones N . Matrix metalloproteinase 3 is a mediator of pulmonary fibrosis. Am J Pathol. 2011; 179(4):1733-45. PMC: 3181358. DOI: 10.1016/j.ajpath.2011.06.041. View

Gasque P, Jaffar Bandjee M, Mercado Reyes M, Viasus D . Chikungunya Pathogenesis: From the Clinics to the Bench. J Infect Dis. 2016; 214(suppl 5):S446-S448. DOI: 10.1093/infdis/jiw362. View

Waghray M, Cui Z, Horowitz J, Subramanian I, Martinez F, Toews G . Hydrogen peroxide is a diffusible paracrine signal for the induction of epithelial cell death by activated myofibroblasts. FASEB J. 2005; 19(7):854-6. DOI: 10.1096/fj.04-2882fje. View

10.

Bedoui Y, Lebeau G, Guillot X, Dargai F, Guiraud P, Neal J . Emerging Roles of Perivascular Mesenchymal Stem Cells in Synovial Joint Inflammation. J Neuroimmune Pharmacol. 2020; 15(4):838-851. DOI: 10.1007/s11481-020-09958-z. View

11.

Ceradini D, Kulkarni A, Callaghan M, Tepper O, Bastidas N, Kleinman M . Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med. 2004; 10(8):858-64. DOI: 10.1038/nm1075. View

12.

Mazur W, Lindholm P, Vuorinen K, Myllarniemi M, Salmenkivi K, Kinnula V . Cell-specific elevation of NRF2 and sulfiredoxin-1 as markers of oxidative stress in the lungs of idiopathic pulmonary fibrosis and non-specific interstitial pneumonia. APMIS. 2010; 118(9):703-12. DOI: 10.1111/j.1600-0463.2010.02646.x. View

13.

Kuninty P, Bojmar L, Tjomsland V, Larsson M, Storm G, Ostman A . MicroRNA-199a and -214 as potential therapeutic targets in pancreatic stellate cells in pancreatic tumor. Oncotarget. 2016; 7(13):16396-408. PMC: 4941323. DOI: 10.18632/oncotarget.7651. View

14.

da Silva-Neto P, do Valle V, Fuzo C, Fernandes T, Toro D, Fraga-Silva T . Matrix Metalloproteinases on Severe COVID-19 Lung Disease Pathogenesis: Cooperative Actions of MMP-8/MMP-2 Axis on Immune Response through HLA-G Shedding and Oxidative Stress. Biomolecules. 2022; 12(5). PMC: 9138255. DOI: 10.3390/biom12050604. View

15.

Duffield J . Cellular and molecular mechanisms in kidney fibrosis. J Clin Invest. 2014; 124(6):2299-306. PMC: 4038570. DOI: 10.1172/JCI72267. View

16.

Roderburg C, Urban G, Bettermann K, Vucur M, Zimmermann H, Schmidt S . Micro-RNA profiling reveals a role for miR-29 in human and murine liver fibrosis. Hepatology. 2010; 53(1):209-18. DOI: 10.1002/hep.23922. View

17.

Chen Q, Shou P, Zheng C, Jiang M, Cao G, Yang Q . Fate decision of mesenchymal stem cells: adipocytes or osteoblasts?. Cell Death Differ. 2016; 23(7):1128-39. PMC: 4946886. DOI: 10.1038/cdd.2015.168. View

18.

Giannandrea M, Parks W . Diverse functions of matrix metalloproteinases during fibrosis. Dis Model Mech. 2014; 7(2):193-203. PMC: 3917240. DOI: 10.1242/dmm.012062. View

19.

Savary G, Dewaeles E, Diazzi S, Buscot M, Nottet N, Fassy J . The Long Noncoding RNA DNM3OS Is a Reservoir of FibromiRs with Major Functions in Lung Fibroblast Response to TGF-β and Pulmonary Fibrosis. Am J Respir Crit Care Med. 2019; 200(2):184-198. DOI: 10.1164/rccm.201807-1237OC. View

20.

Liu Y, Chen S, Yu L, Deng Y, Li D, Yu X . Pemafibrate attenuates pulmonary fibrosis by inhibiting myofibroblast differentiation. Int Immunopharmacol. 2022; 108:108728. DOI: 10.1016/j.intimp.2022.108728. View