FOXL1 Regulates Lung Fibroblast Function via Multiple Mechanisms
FOXL1 Regulates Lung Fibroblast Function via Multiple Mechanisms
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DOI：
10.1165/rcmb.2019-0396oc
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发表时间：
2020-12-01
影响因子：
6.4
通讯作者：
Nagase, Takahide
中科院分区：
文献类型：
--
作者：
Miyashita, Naoya;Horie, Masafumi;Nagase, Takahide
成纤维细胞为多个器官提供结构框架，对伤口修复和纤维化过程至关重要。在这里，我们证明了FOXL1（叉头盒L1）的功能作用，FOXL1是一种表征肺成纤维细胞肺起源的转录因子。我们在肺成纤维细胞中检测到与DNA低甲基化和超增强子形成相关的高FOXL1转录物，这与来自其他器官的成纤维细胞相反。正常肺组织的RNA原位杂交和免疫组化结果显示，FOXL1 mRNA和蛋白在粘膜下间质细胞及气道上皮细胞中均有表达。转录组分析显示，FOXL1可以控制一系列增强成纤维细胞功能的基因，包括TAZ（带pdz结合基序的转录辅激活因子）/YAP （yes相关蛋白）特征基因和PDGFR α（血小板衍生生长因子受体α）。肺成纤维细胞中FOXL1的沉默减弱了细胞生长和胶原凝胶收缩能力，强调了FOXL1在纤维增殖反应中的功能重要性。具有临床意义的是，在特发性肺纤维化肺组织的成纤维细胞中发现FOXL1 mRNA表达增加。我们的观察表明FOXL1作为一个关键的转录因子调控肺成纤维细胞的多个功能方面，并参与特发性肺纤维化的发病机制。
Fibroblasts provide a structural framework for multiple organs and are essential for wound repair and fibrotic processes. Here, we demonstrate functional roles of FOXL1 (forkhead box L1), a transcription factor that characterizes the pulmonary origin of lung fibroblasts. We detected high FOXL1 transcripts associated with DNA hypomethylation and super-enhancer formation in lung fibroblasts, which is in contrast with fibroblasts derived from other organs. RNA in situ hybridization and immunohistochemistry in normal lung tissue indicated that FOXL1 mRNA and protein are expressed in submucosal interstitial cells together with airway epithelial cells. Transcriptome analysis revealed that FOXL1 could control a broad array of genes that potentiate fibroblast function, including TAZ (transcriptional coactivator with PDZ-binding motif)/YAP (Yes-associated protein) signature genes and PDGFR alpha (platelet-derived growth factor receptor-alpha). FOXL1 silencing in lung fibroblasts attenuated cell growth and collagen gel contraction capacity, underscoring the functional importance of FOXL1 in fibroproliferative reactions. Of clinical importance, increased FOXL1 mRNA expression was found in fibroblasts of idiopathic pulmonary fibrosis lung tissue. Our observations suggest that FOXL1 regulates multiple functional aspects of lung fibroblasts as a key transcription factor and is involved in idiopathic pulmonary fibrosis pathogenesis.