Autocrine TGF-β-positive feedback in profibrotic AT2-lineage cells plays a crucial role in non-inflammatory lung fibrogenesis

Yasunori Enomoto, Hiroaki Katsura, Takashi Fujimura, Akira Ogata, Saori Baba, Akira Yamaoka, Miho Kihara, Takaya Abe, Osamu Nishimura, Mitsutaka Kadota, Daisuke Hazama, Yugo Tanaka, Yoshimasa Maniwa, Tatsuya Nagano and Mitsuru Morimoto ()
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Yasunori Enomoto: RIKEN Center for Biosystems Dynamics Research
Hiroaki Katsura: RIKEN Center for Biosystems Dynamics Research
Takashi Fujimura: RIKEN Center for Biosystems Dynamics Research
Akira Ogata: RIKEN Center for Biosystems Dynamics Research
Saori Baba: RIKEN Center for Biosystems Dynamics Research
Akira Yamaoka: RIKEN Center for Biosystems Dynamics Research
Miho Kihara: RIKEN Center for Biosystems Dynamics Research
Takaya Abe: RIKEN Center for Biosystems Dynamics Research
Osamu Nishimura: RIKEN Center for Biosystems Dynamics Research
Mitsutaka Kadota: RIKEN Center for Biosystems Dynamics Research
Daisuke Hazama: Kobe University Graduate School of Medicine
Yugo Tanaka: Kobe University Graduate School of Medicine
Yoshimasa Maniwa: Kobe University Graduate School of Medicine
Tatsuya Nagano: Kobe University Graduate School of Medicine
Mitsuru Morimoto: RIKEN Center for Biosystems Dynamics Research

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract The molecular etiology of idiopathic pulmonary fibrosis (IPF) has been extensively investigated to identify new therapeutic targets. Although anti-inflammatory treatments are not effective for patients with IPF, damaged alveolar epithelial cells play a critical role in lung fibrogenesis. Here, we establish an organoid-based lung fibrosis model using mouse and human lung tissues to assess the direct communication between damaged alveolar type II (AT2)-lineage cells and lung fibroblasts by excluding immune cells. Using this in vitro model and mouse genetics, we demonstrate that bleomycin causes DNA damage and activates p53 signaling in AT2-lineage cells, leading to AT2-to-AT1 transition-like state with a senescence-associated secretory phenotype (SASP). Among SASP-related factors, TGF-β plays an exclusive role in promoting lung fibroblast-to-myofibroblast differentiation. Moreover, the autocrine TGF-β-positive feedback loop in AT2-lineage cells is a critical cellular system in non-inflammatory lung fibrogenesis. These findings provide insights into the mechanism of IPF and potential therapeutic targets.

Date: 2023
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DOI: 10.1038/s41467-023-40617-y

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