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Lung endothelial cells regulate pulmonary fibrosis through FOXF1/R-Ras signaling

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE213018 | GEO | 2022/09/16

REPOSITORIES: GEO

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Lung endothelial cells regulate pulmonary fibrosis through FOXF1/R-Ras signaling.

Project description:Pulmonary fibrosis results from dysregulated lung repair and involves multiple cell types. The role of endothelial cells (EC) in lung fibrosis is poorly understood. Using single cell RNA-sequencing we identified endothelial transcription factors involved in lung fibrogenesis, including FOXF1, SMAD6, ETV6 and LEF1. Focusing on FOXF1, we found that FOXF1 is decreased in EC within human idiopathic pulmonary fibrosis (IPF) and mouse bleomycin-injured lungs. Endothelial-specific Foxf1 inhibition in mice increased collagen depositions, promoted lung inflammation, and impaired R-Ras signaling. In vitro, FOXF1-deficient EC increased proliferation, invasion and activation of human lung fibroblasts, and stimulated macrophage migration by secreting IL-6, TNFα, CCL2 and CXCL1. FOXF1 inhibited TNFα and CCL2 through direct transcriptional activation of Rras gene promoter. Transgenic overexpression or endothelial-specific nanoparticle delivery of Foxf1 cDNA decreased pulmonary fibrosis in bleomycin-injured mice. Nanoparticle delivery of FOXF1 cDNA can be considered for future therapies in IPF.

| S-EPMC10156846 | biostudies-literature

Lung endothelial cells regulate pulmonary fibrosis through FOXF1/R-Ras signaling (Human).

Project description:Pulmonary fibrosis results from dysregulated repair of damaged tissue caused by persistent injury of lung epithelium. Multiple cell types in the lung are involved in the process of repair. During lung fibrogenesis, normal endothelial cells (EC) are re-programmed into fibrosis-associated EC. Transcriptional factors that control re-programming are poorly understood. Using single cell RNA-sequencing of EC from donor and idiopathic pulmonary fibrosis (IPF) lungs, and lungs from bleomycin-treated mice, we identified endothelial transcription factors (TF) that were differentially expressed during fibrosis. Focusing on one of endothelial TF, FOXF1, we demonstrated that FOXF1 is decreased in EC within human IPF and mouse bleomycin-injured fibrotic lungs.

2022-09-16 | GSE213017 | GEO

Lung endothelial cells regulate pulmonary fibrosis through FOXF1/R-Ras signaling (Mouse I).

2022-09-16 | GSE213016 | GEO

Lung endothelial cells regulate pulmonary fibrosis through FOXF1/R-Ras signaling (Mouse II).

2022-09-16 | GSE213279 | GEO

Lung endothelial cells regulate pulmonary fibrosis through FOXF1/R-Ras signaling

Project description:Lung endothelial cells regulate pulmonary fibrosis through FOXF1/R-Ras signaling

| PRJNA878780 | ENA

Lung endothelial cells regulate pulmonary fibrosis through FOXF1/R-Ras signaling (Human).

Project description:Lung endothelial cells regulate pulmonary fibrosis through FOXF1/R-Ras signaling (Human).

| PRJNA878787 | ENA

Lung endothelial cells regulate pulmonary fibrosis through FOXF1/R-Ras signaling (Mouse II).

Project description:Lung endothelial cells regulate pulmonary fibrosis through FOXF1/R-Ras signaling (Mouse II).

| PRJNA880322 | ENA

Lung endothelial cells regulate pulmonary fibrosis through FOXF1/R-Ras signaling (Mouse I).

Project description:Lung endothelial cells regulate pulmonary fibrosis through FOXF1/R-Ras signaling (Mouse I).

| PRJNA878788 | ENA

Endothelial progenitor cells stimulate neonatal lung angiogenesis through FOXF1-mediated activation of BMP9/ACVRL1 signaling.

Project description:Pulmonary endothelial progenitor cells (EPCs) are critical for neonatal lung angiogenesis and represent a subset of general capillary cells (gCAPs). Molecular mechanisms through which EPCs stimulate lung angiogenesis are unknown. Herein, we used single-cell RNA sequencing to identify the BMP9/ACVRL1/SMAD1 pathway signature in pulmonary EPCs. BMP9 receptor, ACVRL1, and its downstream target genes were inhibited in EPCs from Foxf1WT/S52F mutant mice, a model of alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). Expression of ACVRL1 and its targets were reduced in lungs of ACDMPV subjects. Inhibition of FOXF1 transcription factor reduced BMP9/ACVRL1 signaling and decreased angiogenesis in vitro. FOXF1 synergized with ETS transcription factor FLI1 to activate ACVRL1 promoter. Nanoparticle-mediated silencing of ACVRL1 in newborn mice decreased neonatal lung angiogenesis and alveolarization. Treatment with BMP9 restored lung angiogenesis and alveolarization in ACVRL1-deficient and Foxf1WT/S52F mice. Altogether, EPCs promote neonatal lung angiogenesis and alveolarization through FOXF1-mediated activation of BMP9/ACVRL1 signaling.

| S-EPMC9019054 | biostudies-literature

FOXF1 Inhibits Pulmonary Fibrosis by Preventing CDH2-CDH11 Cadherin Switch in Myofibroblasts.

Project description:Idiopathic pulmonary fibrosis (IPF) is characterized by aberrant accumulation of collagen-secreting myofibroblasts. Development of effective therapies is limited due to incomplete understanding of molecular mechanisms regulating myofibroblast expansion. FOXF1 transcription factor is expressed in resident lung fibroblasts, but its role in lung fibrosis remains unknown due to the lack of genetic mouse models. Through comprehensive analysis of human IPF genomics data, lung biopsies, and transgenic mice with fibroblast-specific inactivation of FOXF1, we show that FOXF1 inhibits pulmonary fibrosis. FOXF1 deletion increases myofibroblast invasion and collagen secretion and promotes a switch from N-cadherin (CDH2) to Cadherin-11 (CDH11), which is a critical step in the acquisition of the pro-fibrotic phenotype. FOXF1 directly binds to Cdh2 and Cdh11 promoters and differentially regulates transcription of these genes. Re-expression of CDH2 or inhibition of CDH11 in FOXF1-deficient cells reduces myofibroblast invasion in vitro. FOXF1 inhibits pulmonary fibrosis by regulating a switch from CDH2 to CDH11 in lung myofibroblasts.

| S-EPMC5947867 | biostudies-literature

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