Identification of paired-related Homeobox Protein 1 as a key mesenchymal transcription factor in pulmonary fibrosis
- Université Paris Cité, Inserm, France
- Université Catholique de Louvain, Belgium
- Univ Rennes, Inserm, EHESP, France
- Assistance Publique - Hôpitaux de Paris, France
- Collège de France, CNRS-UMR7241, INSERM-U1050, PSL Research University,, France
- Université Côte d'Azur, CNRS, France
- Secarna Pharmaceuticals GmbH and Co KG, Germany
- University of Giessen, Germany
Abstract
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-b/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.
Data availability
For gene expression profiling, publicly available datasets were obtained from NCBI Gene Expression Omnibus (GSE2052, GSE24206 and GSE21411) , IPF Cell Atlas (www.ipfcellatlas.com) or FibroXplorer (www.fibroXplorer.com). Newly generated expression dataset has been deposited in the Gene Expression Omnibus GSE161364. All data generated or analyzed during this study are included in the manuscript and supporting files.
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IPF versus ControlNCBI Gene Expression Omnibus, GSE2052.
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Validated Gene Expression Signatures of Idiopathic Pulmonary FibrosisNCBI Gene Expression Omnibus, GSE24206.
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Systems biology of interstitial lung diseasesNCBI Gene Expression Omnibus, GSE21411.
Article and author information
Author details
Funding
Agence Nationale de la Recherche (JCJC ANR-16-CE14-00)
- Arnaud A Mailleux
European Respiratory Society (ERS-LTRF 2015 - 4476)
- Antoine Froidure
Fondation pour la Recherche Médicale (FDT2021060129750)
- Méline Homps-Legrand
Fondation pour la Recherche Médicale (FDM41320)
- Aurélien Justet
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal experiments were conducted in accordance with the Directive 2010/63/EU of the European Parliament and approved by the local Animal ethics committee ("Comité d'éthique Paris Nord 121", APAFiS #4778 Etudedufacteurdetran_2016031617411315).
Human subjects: The study on human material was performed in accordance with the Declaration of Helsinki and approved by the local ethics committee (CPP Ile de France 1, No.0811760). Written informed consent was obtained from all subjects.
Copyright
© 2023, Marchal-Duval et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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