Identification of Paired-related Homeobox Protein 1 as a key mesenchymal transcription factor in Idiopathic Pulmonary Fibrosis

Marchal-Duval, E.; Homps-Legrand, M.; Froidure, A.; Jaillet, M.; Ghanem, M.; Deneuville, L.; Justet, A.; Maurac, A.; Vadel, A.; Fortas, E.; Cazes, A.; Joannes, A.; Giersch, L.; Mal, H.; Mordant, P.; Mounier, C. M.; Schirduan, X.; Korfei, M.; Gunther, A.; Mari, B.; Jaschinski, F.; Crestani, B.; Mailleux, A. A.

doi:10.1101/2021.01.15.425870

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bioRxiv · 10.1101/2021.01.15.425870

Identification of Paired-related Homeobox Protein 1 as a key mesenchymal transcription factor in Idiopathic Pulmonary Fibrosis

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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-{beta}/PGE2 balance in vitro in control and IPF fibroblasts, while IPF fibroblast-derived matrix increased PRRX1 expression in a PDGFR dependent manner in control ones. PRRX1 inhibition decreased fibroblast proliferation by downregulating the expression of S phase cyclins. PRRX1 inhibition also impacted TGF-{beta} driven myofibroblastic differentiation by inhibiting SMAD2/3 phosphorylation through phosphatase PPM1A upregulation and TGFBR2 downregulation, leading to TGF-{beta} 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 precision-cut lung slices. Our results identified PRRX1 as a mesenchymal transcription factor driving lung fibrogenesis. Brief SummaryInhibition of a single fibroblast-associated transcription factor, namely paired-related homeobox protein 1, is sufficient to dampen lung fibrogenesis.

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Marchal-Duval, E., Homps-Legrand, M., Froidure, A., Jaillet, M., Ghanem, M., Deneuville, L., Justet, A., Maurac, A., Vadel, A., Fortas, E., Cazes, A., Joannes, A., Giersch, L., Mal, H., Mordant, P., Mounier, C. M., Schirduan, X., Korfei, M., Gunther, A., Mari, B., Jaschinski, F., Crestani, B., Mailleux, A. A.. 2021-01-15. Identification of Paired-related Homeobox Protein 1 as a key mesenchymal transcription factor in Idiopathic Pulmonary Fibrosis. https://doi.org/10.1101/2021.01.15.425870

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