Fondation Saint-Luc

Cells of mesenchymal origin play an active role in Idiopathic pulmonary fibrosis (IPF). PRRX1 is a mesenchymal transcription factor (TF), known to be implicated in embryonic development, and recently involved in liver fibrosis. The PRRX1 gene encodes two isoforms: PRRX-1a and PRRX-1b. PRRX1 TFs has been described to be at the center of a transcriptional regulatory network, regulating the skin fibroblast phenotype. In a preliminary Transcriptomic Public database analysis, we observed that PRRX1 was upregulated in IPF lung. Thus, we hypothesized that PRRX1 TFs are implicated in IPF development. <b>Methods:</b> We characterized PRRX1 TFs expression in IPF or control lung tissue. Then, we assayed the PRRX1 regulation in IPF or control primary human lung fibroblasts (HLF) using pro or anti-fibrotic soluble factors. We observed PRRX1 mechanoregulation by using in vitro-generated ECM as well as soft or stiff matrix gel. Finally, PRRX1 function was studied by a gain and loss of function approach. <b>Results:</b> Both isoforms of PRRX1 were up-regulated in lung tissue and in HLF from IPF patients as compared to controls. PRRX1 expression was up-regulated in vitro by anti-fibrotic factor PGE2 and culture on soft substrate. While pro-fibrotic factor TGFß and culture on stiff matrix decrease PRRX1. IPF derived ECM increased PRRX1 in control HLF. Finally we demonstrated that PRRX1 modulates fibroblast proliferation, migration and myofibroblastic differentiation in vitro. <b>Conclusion:</b> Our results indicate that PRRX1 TFs expressed by lung fibroblasts are regulated by fibrotic factors and may participate to IPF development by keeping fibroblast in a proliferative and undifferentiated phenotype.

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