| 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
|
| Resource |
| Mice |
RBRC09921 |
