Low let-7d exosomes from pulmonary vascular endothelial cells drive lung pericyte fibrosis through the TGFβRI/FoxM1/Smad/β-catenin pathway
© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd..
The pathogenesis of pulmonary fibrosis (PF) was mediated by the progressive deposition of excessive extracellular matrix, but little is known about the regulatory mechanisms of fibrogenesis by lung pericytes. The mouse PF model was established by treatment with bleomycin, followed by isolation of exosomes from mouse broncho-alveolar lavage fluids by the centrifuge method. Relative mRNA/microRNA levels and protein expression were assessed by qRT-PCR and Western blotting, respectively. The binding of let-7d with gene promoter was validated by dual-luciferase reporter assay. Protein interactions were verified via GST pull-down and co-immunoprecipitation. Nuclear retention of Smad3 was analysed by extraction of cytoplasmic and nuclear fraction of pericytes followed by Western blotting. Association of FoxM1 with gene promoter was detected by EMSA and ChIP-PCR methods. FoxM1 expression is significantly elevated in human lung fibroblasts of PF patients and mouse PF model. The expression of let-7d is repressed in exosomes derived from broncho-alveolar lavage fluids of PF mice. Let-7d or FoxM1 knockdown suppressed the expression of FoxM1, Smad3, β-catenin, Col1A and α-SMA expression in mouse lung pericytes under TGF-β1 treatment. FoxM1 overexpression elevated above gene expression in mouse lung pericytes under TGF-β1 treatment. Let-7d directly targets TGFβRI to regulate FoxM1 and downstream gene expression in mouse lung pericytes. FoxM1 directly interacts with Smad3 proteins to promote Smad3 nuclear retention and binds with β-catenin promoter sequence to promote fibrogenesis. Exosomes with low let-7d from pulmonary vascular endothelial cells drive lung pericyte fibrosis through activating the TGFβRI/FoxM1/Smad/β-catenin signalling pathway.
Medienart: |
E-Artikel |
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Erscheinungsjahr: |
2020 |
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Erschienen: |
2020 |
Enthalten in: |
Zur Gesamtaufnahme - volume:24 |
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Enthalten in: |
Journal of cellular and molecular medicine - 24(2020), 23 vom: 01. Dez., Seite 13913-13926 |
Sprache: |
Englisch |
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Beteiligte Personen: |
Xie, Han [VerfasserIn] |
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Links: |
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Anmerkungen: |
Date Completed 12.05.2021 Date Revised 05.10.2022 published: Print-Electronic Citation Status MEDLINE |
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doi: |
10.1111/jcmm.15989 |
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funding: |
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Förderinstitution / Projekttitel: |
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PPN (Katalog-ID): |
NLM317474197 |
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245 | 1 | 0 | |a Low let-7d exosomes from pulmonary vascular endothelial cells drive lung pericyte fibrosis through the TGFβRI/FoxM1/Smad/β-catenin pathway |
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520 | |a The pathogenesis of pulmonary fibrosis (PF) was mediated by the progressive deposition of excessive extracellular matrix, but little is known about the regulatory mechanisms of fibrogenesis by lung pericytes. The mouse PF model was established by treatment with bleomycin, followed by isolation of exosomes from mouse broncho-alveolar lavage fluids by the centrifuge method. Relative mRNA/microRNA levels and protein expression were assessed by qRT-PCR and Western blotting, respectively. The binding of let-7d with gene promoter was validated by dual-luciferase reporter assay. Protein interactions were verified via GST pull-down and co-immunoprecipitation. Nuclear retention of Smad3 was analysed by extraction of cytoplasmic and nuclear fraction of pericytes followed by Western blotting. Association of FoxM1 with gene promoter was detected by EMSA and ChIP-PCR methods. FoxM1 expression is significantly elevated in human lung fibroblasts of PF patients and mouse PF model. The expression of let-7d is repressed in exosomes derived from broncho-alveolar lavage fluids of PF mice. Let-7d or FoxM1 knockdown suppressed the expression of FoxM1, Smad3, β-catenin, Col1A and α-SMA expression in mouse lung pericytes under TGF-β1 treatment. FoxM1 overexpression elevated above gene expression in mouse lung pericytes under TGF-β1 treatment. Let-7d directly targets TGFβRI to regulate FoxM1 and downstream gene expression in mouse lung pericytes. FoxM1 directly interacts with Smad3 proteins to promote Smad3 nuclear retention and binds with β-catenin promoter sequence to promote fibrogenesis. Exosomes with low let-7d from pulmonary vascular endothelial cells drive lung pericyte fibrosis through activating the TGFβRI/FoxM1/Smad/β-catenin signalling pathway | ||
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