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

Author

Listed:
  • Fenghua Bian

    (the Perinatal Institute of Cincinnati Children’s Research Foundation)

  • Ying-Wei Lan

    (the Perinatal Institute of Cincinnati Children’s Research Foundation)

  • Shuyang Zhao

    (the Perinatal Institute of Cincinnati Children’s Research Foundation)

  • Zicheng Deng

    (the Perinatal Institute of Cincinnati Children’s Research Foundation
    Cincinnati Children’s Hospital Medical Center
    College of Engineering and Applied Science, University of Cincinnati)

  • Samriddhi Shukla

    (the Perinatal Institute of Cincinnati Children’s Research Foundation)

  • Anusha Acharya

    (the Perinatal Institute of Cincinnati Children’s Research Foundation)

  • Johnny Donovan

    (the Perinatal Institute of Cincinnati Children’s Research Foundation)

  • Tien Le

    (the Perinatal Institute of Cincinnati Children’s Research Foundation)

  • David Milewski

    (the Perinatal Institute of Cincinnati Children’s Research Foundation)

  • Matthew Bacchetta

    (Vanderbilt University Medical Center)

  • Ahmed Emad Hozain

    (State University of New York Downstate Medical Center)

  • Yuliya Tipograf

    (State University of New York Downstate Medical Center)

  • Ya-Wen Chen

    (Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai)

  • Yan Xu

    (the Perinatal Institute of Cincinnati Children’s Research Foundation
    University of Cincinnati College of Medicine)

  • Donglu Shi

    (College of Engineering and Applied Science, University of Cincinnati)

  • Vladimir V. Kalinichenko

    (the Perinatal Institute of Cincinnati Children’s Research Foundation
    Cincinnati Children’s Hospital Medical Center
    University of Cincinnati College of Medicine)

  • Tanya V. Kalin

    (the Perinatal Institute of Cincinnati Children’s Research Foundation
    University of Cincinnati College of Medicine)

Abstract

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.

Suggested Citation

  • Fenghua Bian & Ying-Wei Lan & Shuyang Zhao & Zicheng Deng & Samriddhi Shukla & Anusha Acharya & Johnny Donovan & Tien Le & David Milewski & Matthew Bacchetta & Ahmed Emad Hozain & Yuliya Tipograf & Ya, 2023. "Lung endothelial cells regulate pulmonary fibrosis through FOXF1/R-Ras signaling," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38177-2
    DOI: 10.1038/s41467-023-38177-2
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