Endothelial cells regulate alveolar morphogenesis by constructing basement membranes acting as a scaffold for myofibroblasts
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 demonstrate...
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2024-03-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-45910-y |
| _version_ | 1797274059646435328 |
|---|---|
| author | Haruko Watanabe-Takano Katsuhiro Kato Eri Oguri-Nakamura Tomohiro Ishii Koji Kobayashi Takahisa Murata Koichiro Tsujikawa Takaki Miyata Yoshiaki Kubota Yasuyuki Hanada Koichi Nishiyama Tetsuro Watabe Reinhard Fässler Hirotaka Ishii Naoki Mochizuki Shigetomo Fukuhara |
| author_facet | Haruko Watanabe-Takano Katsuhiro Kato Eri Oguri-Nakamura Tomohiro Ishii Koji Kobayashi Takahisa Murata Koichiro Tsujikawa Takaki Miyata Yoshiaki Kubota Yasuyuki Hanada Koichi Nishiyama Tetsuro Watabe Reinhard Fässler Hirotaka Ishii Naoki Mochizuki Shigetomo Fukuhara |
| author_sort | Haruko Watanabe-Takano |
| collection | DOAJ |
| description | 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 (Rap1 iECKO ) mice exhibit impaired septa formation and hypo-alveolarization due to the decreased mechanical signaling in myofibroblasts. In Rap1 iECKO 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. |
| first_indexed | 2024-03-07T14:52:58Z |
| format | Article |
| id | doaj.art-d8d2000ac9cf426285f51d72b422c366 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-07T14:52:58Z |
| publishDate | 2024-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-d8d2000ac9cf426285f51d72b422c3662024-03-05T19:37:44ZengNature PortfolioNature Communications2041-17232024-03-0115111910.1038/s41467-024-45910-yEndothelial cells regulate alveolar morphogenesis by constructing basement membranes acting as a scaffold for myofibroblastsHaruko Watanabe-Takano0Katsuhiro Kato1Eri Oguri-Nakamura2Tomohiro Ishii3Koji Kobayashi4Takahisa Murata5Koichiro Tsujikawa6Takaki Miyata7Yoshiaki Kubota8Yasuyuki Hanada9Koichi Nishiyama10Tetsuro Watabe11Reinhard Fässler12Hirotaka Ishii13Naoki Mochizuki14Shigetomo Fukuhara15Department of Molecular Pathophysiology, Institute of Advanced Medical Sciences, Nippon Medical SchoolDepartment of Cardiology, Graduate School of Medicine, Nagoya UniversityDepartment of Molecular Pathophysiology, Institute of Advanced Medical Sciences, Nippon Medical SchoolDepartment of Molecular Pathophysiology, Institute of Advanced Medical Sciences, Nippon Medical SchoolDepartment of Animal Radiology, Graduate School of Agricultural and Life Sciences, University of TokyoDepartment of Animal Radiology, Graduate School of Agricultural and Life Sciences, University of TokyoDepartment of Anatomy and Cell Biology, Graduate School of Medicine, Nagoya UniversityDepartment of Anatomy and Cell Biology, Graduate School of Medicine, Nagoya UniversityDepartment of Anatomy, Keio University School of MedicineDepartment of Cardiology, Graduate School of Medicine, Nagoya UniversityLaboratory for Vascular and Cellular Dynamics, Department of Medical Sciences, University of MiyazakiDepartment of Biochemistry, Graduate, School of Medical and Dental Sciences, Tokyo Medical and Dental UniversityDepartment of Molecular Medicine, Max Planck Institute of BiochemistryDepartment of Anatomy and Neurobiology, Graduate School of Medicine, Nippon Medical SchoolDepartment of Cell Biology, National Cerebral and Cardiovascular Center Research InstituteDepartment of Molecular Pathophysiology, Institute of Advanced Medical Sciences, Nippon Medical SchoolAbstract 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 (Rap1 iECKO ) mice exhibit impaired septa formation and hypo-alveolarization due to the decreased mechanical signaling in myofibroblasts. In Rap1 iECKO 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.https://doi.org/10.1038/s41467-024-45910-y |
| spellingShingle | Haruko Watanabe-Takano Katsuhiro Kato Eri Oguri-Nakamura Tomohiro Ishii Koji Kobayashi Takahisa Murata Koichiro Tsujikawa Takaki Miyata Yoshiaki Kubota Yasuyuki Hanada Koichi Nishiyama Tetsuro Watabe Reinhard Fässler Hirotaka Ishii Naoki Mochizuki Shigetomo Fukuhara Endothelial cells regulate alveolar morphogenesis by constructing basement membranes acting as a scaffold for myofibroblasts Nature Communications |
| title | Endothelial cells regulate alveolar morphogenesis by constructing basement membranes acting as a scaffold for myofibroblasts |
| title_full | Endothelial cells regulate alveolar morphogenesis by constructing basement membranes acting as a scaffold for myofibroblasts |
| title_fullStr | Endothelial cells regulate alveolar morphogenesis by constructing basement membranes acting as a scaffold for myofibroblasts |
| title_full_unstemmed | Endothelial cells regulate alveolar morphogenesis by constructing basement membranes acting as a scaffold for myofibroblasts |
| title_short | Endothelial cells regulate alveolar morphogenesis by constructing basement membranes acting as a scaffold for myofibroblasts |
| title_sort | endothelial cells regulate alveolar morphogenesis by constructing basement membranes acting as a scaffold for myofibroblasts |
| url | https://doi.org/10.1038/s41467-024-45910-y |
| work_keys_str_mv | AT harukowatanabetakano endothelialcellsregulatealveolarmorphogenesisbyconstructingbasementmembranesactingasascaffoldformyofibroblasts AT katsuhirokato endothelialcellsregulatealveolarmorphogenesisbyconstructingbasementmembranesactingasascaffoldformyofibroblasts AT eriogurinakamura endothelialcellsregulatealveolarmorphogenesisbyconstructingbasementmembranesactingasascaffoldformyofibroblasts AT tomohiroishii endothelialcellsregulatealveolarmorphogenesisbyconstructingbasementmembranesactingasascaffoldformyofibroblasts AT kojikobayashi endothelialcellsregulatealveolarmorphogenesisbyconstructingbasementmembranesactingasascaffoldformyofibroblasts AT takahisamurata endothelialcellsregulatealveolarmorphogenesisbyconstructingbasementmembranesactingasascaffoldformyofibroblasts AT koichirotsujikawa endothelialcellsregulatealveolarmorphogenesisbyconstructingbasementmembranesactingasascaffoldformyofibroblasts AT takakimiyata endothelialcellsregulatealveolarmorphogenesisbyconstructingbasementmembranesactingasascaffoldformyofibroblasts AT yoshiakikubota endothelialcellsregulatealveolarmorphogenesisbyconstructingbasementmembranesactingasascaffoldformyofibroblasts AT yasuyukihanada endothelialcellsregulatealveolarmorphogenesisbyconstructingbasementmembranesactingasascaffoldformyofibroblasts AT koichinishiyama endothelialcellsregulatealveolarmorphogenesisbyconstructingbasementmembranesactingasascaffoldformyofibroblasts AT tetsurowatabe endothelialcellsregulatealveolarmorphogenesisbyconstructingbasementmembranesactingasascaffoldformyofibroblasts AT reinhardfassler endothelialcellsregulatealveolarmorphogenesisbyconstructingbasementmembranesactingasascaffoldformyofibroblasts AT hirotakaishii endothelialcellsregulatealveolarmorphogenesisbyconstructingbasementmembranesactingasascaffoldformyofibroblasts AT naokimochizuki endothelialcellsregulatealveolarmorphogenesisbyconstructingbasementmembranesactingasascaffoldformyofibroblasts AT shigetomofukuhara endothelialcellsregulatealveolarmorphogenesisbyconstructingbasementmembranesactingasascaffoldformyofibroblasts |