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Endothelial cells regulate alveolar morphogenesis by constructing basement membranes acting as a scaffold for myofibroblasts

Author

Listed:
  • Haruko Watanabe-Takano

    (Nippon Medical School)

  • Katsuhiro Kato

    (Nagoya University)

  • Eri Oguri-Nakamura

    (Nippon Medical School)

  • Tomohiro Ishii

    (Nippon Medical School)

  • Koji Kobayashi

    (University of Tokyo)

  • Takahisa Murata

    (University of Tokyo)

  • Koichiro Tsujikawa

    (Nagoya University)

  • Takaki Miyata

    (Nagoya University)

  • Yoshiaki Kubota

    (Keio University School of Medicine)

  • Yasuyuki Hanada

    (Nagoya University
    University of Miyazaki)

  • Koichi Nishiyama

    (University of Miyazaki)

  • Tetsuro Watabe

    (Tokyo Medical and Dental University)

  • Reinhard Fässler

    (Max Planck Institute of Biochemistry)

  • Hirotaka Ishii

    (Nippon Medical School)

  • Naoki Mochizuki

    (National Cerebral and Cardiovascular Center Research Institute)

  • Shigetomo Fukuhara

    (Nippon Medical School)

Abstract

Alveologenesis is a spatially coordinated morphogenetic event, during which alveolar myofibroblasts surround the terminal sacs constructed by epithelial cells and endothelial cells (ECs), then contract to form secondary septa to generate alveoli in the lungs. Recent studies have demonstrated the important role of alveolar ECs in this morphogenetic event. However, the mechanisms underlying EC-mediated alveologenesis remain unknown. Herein, we show that ECs regulate alveologenesis by constructing basement membranes (BMs) acting as a scaffold for myofibroblasts to induce septa formation through activating mechanical signaling. Rap1, a small GTPase of the Ras superfamily, is known to stimulate integrin-mediated cell adhesions. EC-specific Rap1-deficient (Rap1iECKO) mice exhibit impaired septa formation and hypo-alveolarization due to the decreased mechanical signaling in myofibroblasts. In Rap1iECKO mice, ECs fail to stimulate integrin β1 to recruit Collagen type IV (Col-4) into BMs required for myofibroblast-mediated septa formation. Consistently, EC-specific integrin β1-deficient mice show hypo-alveolarization, defective mechanical signaling in myofibroblasts, and disorganized BMs. These data demonstrate that alveolar ECs promote integrin β1-mediated Col-4 recruitment in a Rap1-dependent manner, thereby constructing BMs acting as a scaffold for myofibroblasts to induce mechanical signal-mediated alveologenesis. Thus, this study unveils a mechanism of organ morphogenesis mediated by ECs through intrinsic functions.

Suggested Citation

  • Haruko Watanabe-Takano & Katsuhiro Kato & Eri Oguri-Nakamura & Tomohiro Ishii & Koji Kobayashi & Takahisa Murata & Koichiro Tsujikawa & Takaki Miyata & Yoshiaki Kubota & Yasuyuki Hanada & Koichi Nishi, 2024. "Endothelial cells regulate alveolar morphogenesis by constructing basement membranes acting as a scaffold for myofibroblasts," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45910-y
    DOI: 10.1038/s41467-024-45910-y
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    References listed on IDEAS

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