RRC ID 76854
Author Enomoto Y, Katsura H, Fujimura T, Ogata A, Baba S, Yamaoka A, Kihara M, Abe T, Nishimura O, Kadota M, Hazama D, Tanaka Y, Maniwa Y, Nagano T, Morimoto M.
Title Autocrine TGF-β-positive feedback in profibrotic AT2-lineage cells plays a crucial role in non-inflammatory lung fibrogenesis.
Journal Nat Commun
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.
Volume 14(1)
Pages 4956
Published 2023-8-31
DOI 10.1038/s41467-023-40617-y
PII 10.1038/s41467-023-40617-y
PMID 37653024
PMC PMC10471635
MeSH Alveolar Epithelial Cells Animals Cell Differentiation Feedback Humans Idiopathic Pulmonary Fibrosis* / genetics Mice Transforming Growth Factor beta*
IF 12.121
Mice RBRC09921