Glycogen synthase kinase-3β promotes radiation-induced lung fibrosis by regulating β-catenin/lin28 signaling network to determine type II alveolar stem cell transdifferentiation state.
Alveolar Epithelial Cells
/ cytology
Animals
Biomarkers
/ metabolism
Cell Transdifferentiation
Female
Glycogen Synthase Kinase 3 beta
/ physiology
Lung
/ metabolism
Mice
Mice, Inbred C57BL
MicroRNAs
/ metabolism
Pulmonary Fibrosis
/ metabolism
RNA-Binding Proteins
/ metabolism
Radiation Injuries, Experimental
/ metabolism
Stem Cells
/ cytology
beta Catenin
/ metabolism
GSK-3β/TGF-β1/β-catenin
cell differentiation state
lin28/let-7 relative ratios
radiation-induced lung fibrosis
type II alveolar epithelial stem cells
Journal
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
ISSN: 1530-6860
Titre abrégé: FASEB J
Pays: United States
ID NLM: 8804484
Informations de publication
Date de publication:
09 2020
09 2020
Historique:
received:
18
06
2020
accepted:
06
07
2020
pubmed:
25
7
2020
medline:
12
3
2021
entrez:
25
7
2020
Statut:
ppublish
Résumé
The role of type II alveolar epithelial stem cells (AEC II) for alveolar repair in radiation-induced lung fibrosis (RILF) remains largely unknown, mainly because of AEC II phenotype's spontaneous change in vitro. Cell differentiation status is determined by Lin28 and let-7 miRNAs in see-saw-pattern. Lin28, a repressor of let-7 and a stem cell marker, is activated by β-catenin. The expression of β-catenin is regulated by GSK-3β/TGF-β1 signaling. To understand the true role of AEC II in RILF, we freshly isolated primary AEC II directly from thoracically irradiated lungs. We then explored the expressions of cell phenotype markers and differentiation regulators in these isolated AEC II to analyze the correlation between GSK-3β/TGF-β1/β-catenin signaling pathway, lin28/let-7 balance, and AEC II phenotypes at different injury phases following irradiation. Results showed that isolated single primary cells displayed AEC II ultrastructural features and proSP-C positive. The gene expressions of prosp-c (an AEC II biomarker) and hopx (an AEC I marker) significantly increased in isolated AEC II during injury repair phase (P < .001 and P < .05) but decreased at end-stage of injury, while mesenchymal markers increased in both isolated AEC II and irradiated lungs. mRNA levels of gsk-3β, tgf-β1, and β-catenin increased in all irradiated AEC II, but more pronounced in the second half of injury phase (P < .05-P < .001). Similarly, the expression of lin28 was also significantly elevated in isolated AEC II at the late phase (P < .05-P < .001). Four let-7 miRNAs were significantly upregulated in all irradiated AEC II groups (P < .05-P < .001). The time-dependent and highly consistent uptrends for four lin28/let-7 ratios in sorted AEC II contrasted to downtrends in irradiated lungs. In conclusion, RILF occurred when GSK-3β/TGF-β1 signaling increased β-catenin levels, which led to the augmentation of AEC II population by elevated lin28/let-7 ratio and the transcription of profibrotic cytokines and factors, thereby inducing AEC II to undergo transdifferentiation into mesenchymal cells.
Identifiants
pubmed: 32706136
doi: 10.1096/fj.202001518
doi:
Substances chimiques
Biomarkers
0
CTNNB1 protein, mouse
0
Lin-28 protein, mouse
0
MicroRNAs
0
RNA-Binding Proteins
0
beta Catenin
0
mirnlet7 microRNA, mouse
0
Glycogen Synthase Kinase 3 beta
EC 2.7.11.1
Gsk3b protein, mouse
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
12466-12480Informations de copyright
© 2020 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.
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