| Autor: |
Emmeline Marchal-Duval, Méline Homps-Legrand, Antoine Froidure, Madeleine Jaillet, Mada Ghanem, Deneuville Lou, Aurélien Justet, Arnaud Maurac, Aurelie Vadel, Emilie Fortas, Aurelie Cazes, Audrey Joannes, Laura Giersh, Herve Mal, Pierre Mordant, Tristan Piolot, Marin Truchin, Carine M Mounier, Ksenija Schirduan, Martina Korfei, Andreas Gunther, Bernard Mari, Frank Jaschinski, Bruno Crestani, Arnaud A Mailleux |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Předmět: |
|
| Zdroj: |
eLife, Vol 12 (2023) |
| Druh dokumentu: |
article |
| ISSN: |
2050-084X |
| DOI: |
10.7554/eLife.79840 |
| Popis: |
Matrix remodeling is a salient feature of idiopathic pulmonary fibrosis (IPF). Targeting cells driving matrix remodeling could be a promising avenue for IPF treatment. Analysis of transcriptomic database identified the mesenchymal transcription factor PRRX1 as upregulated in IPF. PRRX1, strongly expressed by lung fibroblasts, was regulated by a TGF-β/PGE2 balance in vitro in control and IPF human lung fibroblasts, while IPF fibroblast-derived matrix increased PRRX1 expression in a PDGFR-dependent manner in control ones. PRRX1 inhibition decreased human lung fibroblast proliferation by downregulating the expression of S phase cyclins. PRRX1 inhibition also impacted TGF-β driven myofibroblastic differentiation by inhibiting SMAD2/3 phosphorylation through phosphatase PPM1A upregulation and TGFBR2 downregulation, leading to TGF-β response global decrease. Finally, targeted inhibition of Prrx1 attenuated fibrotic remodeling in vivo with intra-tracheal antisense oligonucleotides in bleomycin mouse model of lung fibrosis and ex vivo using human and mouse precision-cut lung slices. Our results identified PRRX1 as a key mesenchymal transcription factor during lung fibrogenesis. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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