Transcription factor TBX4 regulates myofibroblast accumulation and lung fibrosis
Transcription factor TBX4 regulates myofibroblast accumulation and lung fibrosis
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DOI：
10.1172/jci85328
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发表时间：
2016-08-01
影响因子：
15.9
通讯作者：
Noble, Paul W.
中科院分区：
文献类型：
--
作者：
Xie, Ting;Liang, Jiurong;Noble, Paul W.
进行性组织纤维化是与反复上皮损伤和肌成纤维细胞积累相关的发病和死亡的主要原因。由于对调节肌成纤维细胞积累的分子机制的不完全了解，成功的治疗方案受到限制。在这里，我们采用体内谱系追踪和实时基因表达转基因报告方法来分析早期胚胎转录因子T-box基因4（TBX4），并确定TBX4谱系间充质祖细胞是受损成人肺中肌成纤维细胞的主要来源。在小鼠模型中，消除表达 TBX4 的细胞或破坏 TBX4 信号传导可减轻博莱霉素诱导损伤后的肺纤维化。此外，TBX4 调节乙酰透明质酸合酶 2 的产生，使小鼠模型和严重肺纤维化患者的成纤维细胞能够侵入基质。这些数据表明 TBX4 是一种间充质转录因子，可驱动肌成纤维细胞的积累和肺纤维化的发展。针对 TBX4 和调节成纤维细胞侵袭性的下游因子可能会导致肺纤维化的治疗方法。
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.