TBX4 paves the way for lung fibrosis
Progressive lung fibrosis, particularly the idiopathic form, causes severe pulmonary dysfunction with limited treatment options. While it is known that a combination of epithelial injury, accumulation of activated fibroblasts, and deposition of cellular matrix contribute to this disease, the underlying molecular mechanisms and cellular components remain incompletely characterized. In particular, fibroblast accumulation plays a central role in tissue fibrosis, but the regulation and cellular origins of this facet of disease are unclear. Ting Xie and colleagues of Cedars-Sinai Medical Center have discovered that the embryonic transcription factor TBX4 contributes to lung fibrosis by facilitating fibroblast accumulation. Using in vivo lineage tracing, cell surface marker analysis, and gene expression profiling, the group demonstrated that TBX4-expressing progenitors give rise to a variety of lung cell types, and importantly, are a major source of activated fibroblasts. In a mouse model, TBX4-positive lung fibroblast accumulation was induced in response to chemical-mediated injury and occurred by clonal expansion. Correspondingly, ablation of TBX4-expressing cells or fibroblast-targeted deletion of Tbx4 inhibited lung fibrosis in mice. TBX4 also controlled the pathogenic effect of activated fibroblasts by promoting expression of genes required for fibrinogenesis, hyaluronan synthase 2-associated fibroblast invasion, and hyaluronan production in both mouse fibroblasts and human fibroblasts from patients with severe idiopathic lung fibrosis. These findings indicate that TBX4 plays multiple roles in the accumulation of pathogenic fibroblasts during lung fibrosis, and may be a promising target for future therapeutic strategies. The accompanying image shows Masson’s trichrome staining of lung collagen before (top row) and following (bottom row) chemical-induced pulmonary injury in mice with (right column) or without (left column) fibroblast-targeted Tbx4 deletion. Note the decreased collagen deposition and lung fibrosis in mice with Tbx4 deletion (lower right panel) as compared to WT mice (lower left panel).
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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
Copyright © 2019 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)