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.
-
IPF versus ControlNCBI Gene Expression Omnibus, GSE2052.
-
Validated Gene Expression Signatures of Idiopathic Pulmonary FibrosisNCBI Gene Expression Omnibus, GSE24206.
-
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.
Metrics
-
- 1,129
- views
-
- 225
- downloads
-
- 5
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Identification of paired-related Homeobox Protein 1 as a key mesenchymal transcription factor in pulmonary fibrosis
eLife 12:e79840.
https://doi.org/10.7554/eLife.79840
Further reading
-
- Cell Biology
The accumulation of SIRT4 in the nuclei of kidney cells drives kidney fibrosis, so blocking the movement of this protein could be a potential therapeutic strategy against fibrosis.
-
- Cell Biology
- Developmental Biology
Chondrocyte columns, which are a hallmark of growth plate architecture, play a central role in bone elongation. Columns are formed by clonal expansion following rotation of the division plane, resulting in a stack of cells oriented parallel to the growth direction. In this work, we analyzed hundreds of Confetti multicolor clones in growth plates of mouse embryos using a pipeline comprising 3D imaging and algorithms for morphometric analysis. Surprisingly, analysis of the elevation angles between neighboring pairs of cells revealed that most cells did not display the typical stacking pattern associated with column formation, implying incomplete rotation of the division plane. Morphological analysis revealed that although embryonic clones were elongated, they formed clusters oriented perpendicular to the growth direction. Analysis of growth plates of postnatal mice revealed both complex columns, composed of ordered and disordered cell stacks, and small, disorganized clusters located in the outer edges. Finally, correlation between the temporal dynamics of the ratios between clusters and columns and between bone elongation and expansion suggests that clusters may promote expansion, whereas columns support elongation. Overall, our findings support the idea that modulations of division plane rotation of proliferating chondrocytes determines the formation of either clusters or columns, a multifunctional design that regulates morphogenesis throughout pre- and postnatal bone growth. Broadly, this work provides a new understanding of the cellular mechanisms underlying growth plate activity and bone elongation during development.
