title: Transcription factor TBX4 regulates myofibroblast accumulation and lung fibrosis.
abstract: 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.
authors.forename: Ting
authors.initials: T
authors.lastname: Xie
authors.forename: Jiurong
authors.initials: J
authors.lastname: Liang
authors.forename: Ningshan
authors.initials: N
authors.lastname: Liu
authors.forename: Caijuan
authors.initials: C
authors.lastname: Huan
authors.forename: Yanli
authors.initials: Y
authors.lastname: Zhang
authors.forename: Weijia
authors.initials: W
authors.lastname: Liu
authors.forename: Maya
authors.initials: M
authors.lastname: Kumar
authors.forename: Rui
authors.initials: R
authors.lastname: Xiao
authors.forename: Jeanine
authors.initials: J
authors.lastname: D'Armiento
authors.forename: Daniel
authors.initials: D
authors.lastname: Metzger
authors.forename: Pierre
authors.initials: P
authors.lastname: Chambon
authors.forename: Virginia E
authors.initials: VE
authors.lastname: Papaioannou
authors.forename: Barry R
authors.initials: BR
authors.lastname: Stripp
authors.forename: Dianhua
authors.initials: D
authors.lastname: Jiang
authors.forename: Paul W
authors.initials: PW
authors.lastname: Noble
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000737:chemistry; D019070:Cell Lineage; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D014453:Glucuronosyltransferase / Q000378:metabolism; D006801:Humans; D000076002:Hyaluronan Synthases; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D058628:Myofibroblasts / Q000378:metabolism*; D011658:Pulmonary Fibrosis / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000378:metabolism*; D019076:Transgenes
chemical_list: D020825:T-Box Domain Proteins; C491193:TBX4 protein, human; D001761:Bleomycin; D014453:Glucuronosyltransferase; C491099:Has2 protein, mouse; D000076002:Hyaluronan Synthases