Transcription factor TBX4 regulates myofibroblast accumulation and lung fibrosis.
Fiche publication
Date publication
août 2016
Journal
The Journal of clinical investigation
Auteurs
Membres identifiés du Cancéropôle Est :
Pr CHAMBON Pierre, Dr METZGER Daniel
Tous les auteurs :
Xie T, Liang J, Liu N, Huan C, Zhang Y, Liu W, Kumar M, Xiao R, D'Armiento J, Metzger D, Chambon P, Papaioannou VE, Stripp BR, Jiang D, Noble PW
Lien Pubmed
Résumé
Progressive tissue fibrosis is a major cause of the morbidity and mortality associated with repeated epithelial injuries and accumulation of myofibroblasts. Successful treatment options are limited by an incomplete understanding of the molecular mechanisms that regulate myofibroblast accumulation. Here, we employed in vivo lineage tracing and real-time gene expression transgenic reporting methods to analyze the early embryonic transcription factor T-box gene 4 (TBX4), and determined that TBX4-lineage mesenchymal progenitors are the predominant source of myofibroblasts in injured adult lung. In a murine model, ablation of TBX4-expressing cells or disruption of TBX4 signaling attenuated lung fibrosis after bleomycin-induced injury. Furthermore, TBX4 regulated hyaluronan synthase 2 production to enable fibroblast invasion of matrix both in murine models and in fibroblasts from patients with severe pulmonary fibrosis. These data identify TBX4 as a mesenchymal transcription factor that drives accumulation of myofibroblasts and the development of lung fibrosis. Targeting TBX4 and downstream factors that regulate fibroblast invasiveness could lead to therapeutic approaches in lung fibrosis.
Mots clés
Animals, Bleomycin, chemistry, Cell Lineage, Cell Proliferation, Endothelial Cells, metabolism, Female, Fibroblasts, metabolism, Gene Expression Regulation, Glucuronosyltransferase, metabolism, Humans, Hyaluronan Synthases, Lung, metabolism, Male, Mice, Mice, Inbred C57BL, Microscopy, Confocal, Myofibroblasts, metabolism, Pulmonary Fibrosis, metabolism, Signal Transduction, Stem Cells, metabolism, T-Box Domain Proteins, metabolism, Transgenes
Référence
J. Clin. Invest.. 2016 Aug;126(8):3063-79