Identification of Paired-related Homeobox Protein 1 as a key mesenchymal transcription factor in pulmonary fibrosis.
(2023) eLife — Vol. 12, n° 1, p. 1-32 (2023)
Files
MarchalDuvaletalELife2023.pdf
Open Access - Adobe PDF
- 18.48 MB
Details
- Authors
Mailleux, Arnaud A 
- 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-β/PGE2 balance in vitro in control and IPF human lung fibroblasts, while IPF fibroblast-derived matrix increased 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 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.
- Affiliations
Citations
Marchal-Duval, E., Homps-Legrand, M., Froidure, A., Jaillet, M., Ghanem, M., Lou, D., Justet, A., Maurac, A., Vadel, A., Fortas, E., Cazes, A., Joannes, A., Giersh, L., Mal, H., Mordant, P., Piolot, T., Truchin, M., Mounier, C. M., Schirduan, K., et al. (2023). Identification of Paired-related Homeobox Protein 1 as a key mesenchymal transcription factor in pulmonary fibrosis. eLife, 12(1), 1-32. https://doi.org/10.7554/eLife.79840 (Original work published 2023)