Loss of FOXF1 expression promotes human lung-resident mesenchymal stromal cell migration via ATX/LPA/LPA1 signaling axis.
Loss of FOXF1 expression promotes human lung-resident mesenchymal stromal cell migration via ATX/LPA/LPA1 signaling axis.
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DOI：
10.1038/s41598-020-77601-1
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发表时间：
2020-12-04
影响因子：
4.6
通讯作者：
Lama VN
中科院分区：
文献类型：
--
作者：
Cao P;Walker NM;Braeuer RR;Mazzoni-Putman S;Aoki Y;Misumi K;Wheeler DS;Vittal R;Lama VN
Forkhead box F1(FOXF1)是一种肺胚胎间充质相关转录因子，在成年期间充质基质细胞中持续表达。然而，其在成人肺间充质基质细胞(LR-MSCs)中的生物学功能仍有待阐明。在这里，我们证明FOXF1的表达通过其作为自分泌运动刺激因子自体趋化因子(ATX)的新的转录抑制因子的作用来抑制LR-MSCs的迁移功能。与非纤维化对照相比，纤维化的人LR-MSCs显示FOXF1基因和蛋白的表达降低。RNAi介导的FOXF1沉默与调控增殖、迁移和炎症反应的关键基因上调有关，Boyden小室证实FOXF1沉默的LR-MSCs具有显著更高的迁移能力。ATX是一种分泌型溶血磷脂酶D，主要负责胞外溶血磷脂酸(LPA)的产生，经Affymetrix分析，它是十大上调基因之一。FOXF1沉默的LR-MSCs显示ATX活性增强，而mFoxf1过表达则降低ATX的表达和活性。通过ATX和LPA1受体的遗传和药物靶向，FOXF1沉默诱导的LR-MSC迁移增加被取消。染色质免疫沉淀分析发现，在1.5kb的ATX启动子中有三个假定的FOXF1结合位点，它们证明了ATX表达的转录抑制。总之，这些发现确认FOXF1是ATX的一个新的转录抑制因子，并表明FOXF1的缺失通过ATX/LPA/LPA1信号轴促进LR-MSC的迁移。
Forkhead box F1 (FOXF1) is a lung embryonic mesenchyme-associated transcription factor that demonstrates persistent expression into adulthood in mesenchymal stromal cells. However, its biologic function in human adult lung-resident mesenchymal stromal cells (LR-MSCs) remain to be elucidated. Here, we demonstrate that FOXF1 expression acts as a restraint on the migratory function of LR-MSCs via its role as a novel transcriptional repressor of autocrine motility-stimulating factor Autotaxin (ATX). Fibrotic human LR-MSCs demonstrated lower expression of FOXF1 mRNA and protein, compared to non-fibrotic controls. RNAi-mediated FOXF1 silencing in LR-MSCs was associated with upregulation of key genes regulating proliferation, migration, and inflammatory responses and significantly higher migration were confirmed in FOXF1-silenced LR-MSCs by Boyden chamber. ATX is a secreted lysophospholipase D largely responsible for extracellular lysophosphatidic acid (LPA) production, and was among the top ten upregulated genes upon Affymetrix analysis. FOXF1-silenced LR-MSCs demonstrated increased ATX activity, while mFoxf1 overexpression diminished ATX expression and activity. The FOXF1 silencing-induced increase in LR-MSC migration was abrogated by genetic and pharmacologic targeting of ATX and LPA1 receptor. Chromatin immunoprecipitation analyses identified three putative FOXF1 binding sites in the 1.5 kb ATX promoter which demonstrated transcriptional repression of ATX expression. Together these findings identify FOXF1 as a novel transcriptional repressor of ATX and demonstrate that loss of FOXF1 promotes LR-MSC migration via the ATX/LPA/LPA1 signaling axis.
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影响因子：
5.2
作者：
Badri, Linda;Lama, Vibha N.
通讯作者：
Lama, Vibha N.
DOI：
10.4049/jimmunol.1302831
发表时间：
2014-02-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Knowlden S;Georas SN
通讯作者：
Georas SN
影响因子：
8.8
作者：
Black M;Milewski D;Le T;Ren X;Xu Y;Kalinichenko VV;Kalin TV
通讯作者：
Kalin TV
影响因子：
8
作者：
Chen, M;O'Connor, KL
通讯作者：
O'Connor, KL
DOI：
10.4161/cc.8.22.9937
发表时间：
2009-11-15
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
Liu S;Murph M;Panupinthu N;Mills GB
通讯作者：
Mills GB