Identification of Paired-related Homeobox Protein 1 as a key mesenchymal transcription factor in pulmonary fibrosis.

Marchal-Duval, Emmeline Homps-Legrand, Méline Froidure, Antoine [UCL] 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 et al.[show all]

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.