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Transcription factor TBX4 regulates myofibroblast accumulation and lung fibrosis
Ting Xie, … , Dianhua Jiang, Paul W. Noble
Ting Xie, … , Dianhua Jiang, Paul W. Noble
Published July 11, 2016
Citation Information: J Clin Invest. 2016;126(8):3063-3079. https://doi.org/10.1172/JCI85328.
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Research Article Cell biology Pulmonology

Transcription factor TBX4 regulates myofibroblast accumulation and lung fibrosis

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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

Ting Xie, Jiurong Liang, Ningshan Liu, Caijuan Huan, Yanli Zhang, Weijia Liu, Maya Kumar, Rui Xiao, Jeanine D’Armiento, Daniel Metzger, Pierre Chambon, Virginia E. Papaioannou, Barry R. Stripp, Dianhua Jiang, Paul W. Noble

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Figure 1

Tbx4-lineage cells include smooth muscle cells, fibroblasts, some pericytes, and endothelial cells in both normal and injured lung.

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Tbx4-lineage cells include smooth muscle cells, fibroblasts, some pericy...
(A) Schematic depicting lineage analysis methodology. Tbx4LME-Cre Rosa26-tdTomato mice were used for all experiments in this figure. (B–D) Representative histological sections of Tbx4LME-Cre Rosa26-tdTomato mouse lungs at embryonic d15.5 (B) and uninjured 8-week-old (C) and bleomycin-treated (d21) (D) adult Tbx4LME-Cre Rosa26-tdTomato with Tbx4-lineage cells in red and nuclei in blue. (E) Quantification of Tbx4 lineage tracing, expressed as cells counted in C and D (n = 9 in each group of Tbx4LME-Cre Rosa26-tdTomato mice; ***P ≤ 0.001 by 2-tailed Student’s t test; mean ± SEM). (F–I) Representative immunofluorescent images of adult Tbx4LME-Cre Rosa26-tdTomato mouse lungs, uninjured or bleomycin-treated (d21) and stained with αSMA, desmin, vimentin, COL1α1, PDGFRβ, NG2 (F), lipid acid (G), vWF (H), SPC, T1a, and SCGB1A1 (I) antibody (n = 9 lungs examined). Arrows show cells with overlaps. Scale bars: 100 μm (B–D) and 10 μm (F–I). a, alveoli; aw, airway; bv, blood vessel; f, fibrotic foci; m, mesenchyme; Tomato and Tm, tdTomato.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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