FOXF1 maintains endothelial barrier function and prevents edema after lung injury

Cai, Yuqi; Bolte, Craig; Le, Tien; Goda, Chinmayee; Xu, Yan; Kalin, Tanya V.; Kalinichenko, Vladimir V.

doi:10.1126/scisignal.aad1899

Cited by 75 publications

(75 citation statements)

References 48 publications

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“…This observation is consistent with a proposed model in which cell-type-specific expression of important TF regulators of lineage identity results in nearby hypermethylation ( Li et al, 2018 ). We note that FOXF1, a lung EC-enriched TF implicated in pulmonary vascular development ( Kalinichenko et al, 2001 ; Cai et al, 2016 ; Dharmadhikari et al, 2016 ), represents an exception to this methylation pattern, due to demethylation at the adjacent lung EC-expressed lncRNA gene, Fendrr ( Figure 2—figure supplement 2A ).…”

Section: Resultsmentioning

confidence: 99%

Transcriptional and epigenomic landscapes of CNS and non-CNS vascular endothelial cells

Sabbagh

Heng

Luo

et al. 2018

eLife

202

245

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Vascular endothelial cell (EC) function depends on appropriate organ-specific molecular and cellular specializations. To explore genomic mechanisms that control this specialization, we have analyzed and compared the transcriptome, accessible chromatin, and DNA methylome landscapes from mouse brain, liver, lung, and kidney ECs. Analysis of transcription factor (TF) gene expression and TF motifs at candidate cis-regulatory elements reveals both shared and organ-specific EC regulatory networks. In the embryo, only those ECs that are adjacent to or within the central nervous system (CNS) exhibit canonical Wnt signaling, which correlates precisely with blood-brain barrier (BBB) differentiation and Zic3 expression. In the early postnatal brain, single-cell RNA-seq of purified ECs reveals (1) close relationships between veins and mitotic cells and between arteries and tip cells, (2) a division of capillary ECs into vein-like and artery-like classes, and (3) new endothelial subtype markers, including new validated tip cell markers.

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Section: Resultsmentioning

confidence: 99%

Transcriptional and epigenomic landscapes of CNS and non-CNS vascular endothelial cells

Sabbagh

Heng

Luo

et al. 2018

eLife

202

245

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“…1a), and therefore was not used in subsequent combinations. FOXF2 may act synergistically with FOXF1 43 , which regulates EC barrier of lung ECs 44 . Therefore, it would be interesting in further studies to determine if FOXF2 and FOXF1 simultaneous overexpression would increase EC resistance.…”

Section: Discussionmentioning

confidence: 99%

Identification of a combination of transcription factors that synergistically increases endothelial cell barrier resistance

Roudnicky

Kim

Lan

et al. 2020

Sci Rep

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Endothelial cells (ECs) display remarkable plasticity during development before becoming quiescent and functionally mature. EC maturation is directed by several known transcription factors (TFs), but the specific set of TFs responsible for promoting high-resistance barriers, such as the blood-brain barrier (BBB), have not yet been fully defined. Using expression mRNA data from published studies on ex vivo ECs from the central nervous system (CNS), we predicted TFs that induce high-resistance barrier properties of ECs as in the BBB. We used our previously established method to generate ECs from human pluripotent stem cells (hPSCs), and then we overexpressed the candidate TFs in hPSC-ECs and measured barrier resistance and integrity using electric cell-substrate impedance sensing, trans-endothelial electrical resistance and FITC-dextran permeability assays. SOX18 and TAL1 were the strongest EC barrier-inducing TFs, upregulating Wnt-related signaling and EC junctional gene expression, respectively, and downregulating EC proliferation-related genes. These TFs were combined with SOX7 and ETS1 that together effectively induced EC barrier resistance, decreased paracellular transport and increased protein expression of tight junctions and induce mRNA expression of several genes involved in the formation of EC barrier and transport. Our data shows identification of a transcriptional network that controls barrier resistance in ECs. Collectively this data may lead to novel approaches for generation of in vitro models of the BBB.Endothelial cells (ECs) from different organs display unique molecular 1 and functional 2 profiles. These organotypic profiles arise during endothelial cell development and are directed in part by signals from neighboring cells that activate TFs in ECs to activate or repress specific gene networks 3 . Organotypic differences are pronounced in ECs isolated from the central nervous system (CNS) 1,4-6 that generate the blood-brain barrier (BBB), a highly selective and semipermeable barrier. Unique properties of the BBB include suppressed transcytosis, high tight junction and specialized transporter gene expression, and low immune cell adhesion gene expression 7 . Studies suggest 8-12 that canonical Wnt, Hedgehog and retinoic acid pathways are involved in BBB development. However, other pathways are certainly involved, and the full set of TFs activated in ECs to generate the BBB has not been determined 13,14 . A more complete understanding of TF activation programs in CNS-derived ECs would greatly inform BBB biology.

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“…Sections (5 μm) were stained with hematoxylin and eosin (H&E) to assess gross lung morphology. Immunohistochemical staining and immunofluorescence were performed as described previously [52]. The list of antibodies is presented in S2 Table. Antibody-antigen complexes were detected using biotinylated secondary antibodies followed by avidin-biotin-horseradish peroxidase complex and 3,3'-diaminobenzidine substrate (Vector Labs), as previously described [53], [54].…”

Section: Immunohistochemistry and Immunofluorescencementioning

confidence: 99%

Loss of FOXM1 in macrophages promotes pulmonary fibrosis by activating p38 MAPK signaling pathway

et al. 2020

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Idiopathic pulmonary fibrosis (IPF) is a chronic disease with high mortality and is refractory to treatment. Pulmonary macrophages can both promote and repress fibrosis, however molecular mechanisms regulating macrophage functions during fibrosis remain poorly understood. FOXM1 is a transcription factor and is not expressed in quiescent lungs. Herein, we show that FOXM1 is highly expressed in pulmonary macrophages within fibrotic lungs of IPF patients and mouse fibrotic lungs. Macrophage-specific deletion of Foxm1 in mice (myFoxm1 -/-) exacerbated pulmonary fibrosis. Inactivation of FOXM1 in vivo and in vitro increased p38 MAPK signaling in macrophages and decreased DUSP1, a negative regulator of p38 MAPK pathway. FOXM1 directly activated Dusp1 promoter. Overexpression of DUSP1 in FOXM1-deficient macrophages prevented activation of p38 MAPK pathway. Adoptive transfer of wild-type monocytes to myFoxm1 -/mice alleviated bleomycininduced fibrosis. Altogether, contrary to known pro-fibrotic activities in lung epithelium and fibroblasts, FOXM1 has anti-fibrotic function in macrophages by regulating p38 MAPK. Author summaryIdiopathic pulmonary fibrosis (IPF) is a severe chronic lung disease, which is refractory to treatment. The environmental, age-related, and genetic factors increase susceptibility of the lung to injury. Repeated injury and deregulated repair result in scarring of the lung tissue and ultimate loss of respiratory function. Macrophages are involved at all stages of lung injury and repair, and can promote as well as repress fibrosis. However, molecular mechanisms regulating macrophage functions during fibrosis remain poorly understood. We have previously identified the FOXM1 protein to be highly increased in fibrotic lungs. High levels of FOXM1 in type II epithelial cells and fibroblasts exacerbated pulmonary fibrosis. In the present study, we found a novel and unexpected role of FOXM1. Contrary to pro-fibrotic functions of FOXM1 in epithelial cells and fibroblasts, FOXM1 has an anti- PLOS GENETICSPLOS Genetics | https://doi.fibrotic role in macrophages. Mice lacking FOXM1 in macrophages developed severe pulmonary fibrosis following repeated lung injury with bleomycin. FOXM1 inhibited the p38 MAPK signaling pathway in pulmonary macrophages through transcriptional activation of DUSP1, a negative regulator of p38 MAPK pathway. Adoptive transfer of FOXM1expressing monocytes protected FOXM1-deficient mice from bleomycin-induced pulmonary fibrosis. Altogether, FOXM1 has anti-fibrotic function in macrophages, limiting potential clinical use of FOXM1 inhibitors in IPF.

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FOXF1 maintains endothelial barrier function and prevents edema after lung injury

Cited by 75 publications

References 48 publications

Transcriptional and epigenomic landscapes of CNS and non-CNS vascular endothelial cells

Transcriptional and epigenomic landscapes of CNS and non-CNS vascular endothelial cells

Identification of a combination of transcription factors that synergistically increases endothelial cell barrier resistance

Loss of FOXM1 in macrophages promotes pulmonary fibrosis by activating p38 MAPK signaling pathway

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