Lung fibrogenic microenvironment in mouse reconstitutes human alveolar structure and lung tumor
Ryo Miyata,
Koichi Hasegawa,
Toshi Menju,
Akihiko Yoshizawa,
Akira Watanabe,
Toyohiro Hirai,
Hiroshi Date,
Atsuyasu Sato
Affiliations
Ryo Miyata
Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
Koichi Hasegawa
Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
Toshi Menju
Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
Akihiko Yoshizawa
Department of Diagnostic Pathology, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
Akira Watanabe
Center for iPS Cell Research & Application, Kyoto University, 53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
Toyohiro Hirai
Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
Hiroshi Date
Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
Atsuyasu Sato
Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan; Corresponding author
Summary: A mesenchymal cell activation is a hallmark event of pulmonary fibrosis. Alveolar type 2 (AT2) cells are progenitor cells that maintain alveolar homeostasis, and their damage is assumed to be an initiating event for pulmonary fibrosis. However, the interaction between the lung fibrogenic microenvironment and AT2 cell dynamics remains to be elucidated. Here, we report a unique role of the lung fibrogenic microenvironment, where cell type-specific tissue reconstruction is achieved by exogenous cell transplantation. We found that in the lung fibrogenic microenvironment the AT2 cell pool was depleted, whereas mesenchymal cells could promote intact AT2 cell proliferation in vitro. Furthermore, exogenously transplanted AT2 cells formed alveolar colonies and ameliorated pulmonary fibrosis. Exogenous tumor cells formed tumor nests with relevant histological and transcriptional properties. Human primary cells were adaptable to this microenvironment, facilitating epithelial cell-targeted therapy in pulmonary fibrosis and the establishment of patient-derived xenografts for precision medicine in lung cancer.
