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Identification of Paired-related Homeobox Protein 1 as a key mesenchymal transcription factor in pulmonary fibrosis
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 exp...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10275639/ https://www.ncbi.nlm.nih.gov/pubmed/37261432 http://dx.doi.org/10.7554/eLife.79840 |
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author | Marchal-Duval, Emmeline Homps-Legrand, Méline Froidure, Antoine Jaillet, Madeleine Ghanem, Mada Lou, Deneuville Justet, Aurélien Maurac, Arnaud Vadel, Aurelie Fortas, Emilie Cazes, Aurelie Joannes, Audrey Giersh, Laura Mal, Herve Mordant, Pierre Piolot, Tristan Truchin, Marin Mounier, Carine M Schirduan, Ksenija Korfei, Martina Gunther, Andreas Mari, Bernard Jaschinski, Frank Crestani, Bruno Mailleux, Arnaud A |
author_facet | Marchal-Duval, Emmeline Homps-Legrand, Méline Froidure, Antoine Jaillet, Madeleine Ghanem, Mada Lou, Deneuville Justet, Aurélien Maurac, Arnaud Vadel, Aurelie Fortas, Emilie Cazes, Aurelie Joannes, Audrey Giersh, Laura Mal, Herve Mordant, Pierre Piolot, Tristan Truchin, Marin Mounier, Carine M Schirduan, Ksenija Korfei, Martina Gunther, Andreas Mari, Bernard Jaschinski, Frank Crestani, Bruno Mailleux, Arnaud A |
author_sort | Marchal-Duval, Emmeline |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-10275639 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-102756392023-06-17 Identification of Paired-related Homeobox Protein 1 as a key mesenchymal transcription factor in pulmonary fibrosis Marchal-Duval, Emmeline Homps-Legrand, Méline Froidure, Antoine Jaillet, Madeleine Ghanem, Mada Lou, Deneuville Justet, Aurélien Maurac, Arnaud Vadel, Aurelie Fortas, Emilie Cazes, Aurelie Joannes, Audrey Giersh, Laura Mal, Herve Mordant, Pierre Piolot, Tristan Truchin, Marin Mounier, Carine M Schirduan, Ksenija Korfei, Martina Gunther, Andreas Mari, Bernard Jaschinski, Frank Crestani, Bruno Mailleux, Arnaud A eLife Cell Biology 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. eLife Sciences Publications, Ltd 2023-06-01 /pmc/articles/PMC10275639/ /pubmed/37261432 http://dx.doi.org/10.7554/eLife.79840 Text en © 2023, Marchal-Duval, Homps-Legrand et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Cell Biology Marchal-Duval, Emmeline Homps-Legrand, Méline Froidure, Antoine Jaillet, Madeleine Ghanem, Mada Lou, Deneuville Justet, Aurélien Maurac, Arnaud Vadel, Aurelie Fortas, Emilie Cazes, Aurelie Joannes, Audrey Giersh, Laura Mal, Herve Mordant, Pierre Piolot, Tristan Truchin, Marin Mounier, Carine M Schirduan, Ksenija Korfei, Martina Gunther, Andreas Mari, Bernard Jaschinski, Frank Crestani, Bruno Mailleux, Arnaud A Identification of Paired-related Homeobox Protein 1 as a key mesenchymal transcription factor in pulmonary fibrosis |
title | Identification of Paired-related Homeobox Protein 1 as a key mesenchymal transcription factor in pulmonary fibrosis |
title_full | Identification of Paired-related Homeobox Protein 1 as a key mesenchymal transcription factor in pulmonary fibrosis |
title_fullStr | Identification of Paired-related Homeobox Protein 1 as a key mesenchymal transcription factor in pulmonary fibrosis |
title_full_unstemmed | Identification of Paired-related Homeobox Protein 1 as a key mesenchymal transcription factor in pulmonary fibrosis |
title_short | Identification of Paired-related Homeobox Protein 1 as a key mesenchymal transcription factor in pulmonary fibrosis |
title_sort | identification of paired-related homeobox protein 1 as a key mesenchymal transcription factor in pulmonary fibrosis |
topic | Cell Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10275639/ https://www.ncbi.nlm.nih.gov/pubmed/37261432 http://dx.doi.org/10.7554/eLife.79840 |
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