Inhibition of epithelial cell YAP-TEAD/LOX signaling attenuates pulmonary fibrosis '

Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal disease characterized by excessive extracellular matrix (ECM) deposition. Current IPF therapies slow disease progression but do not stop or reverse it. The (myo)fibroblasts are thought to be the main cellular contributors to excessive ECM production in IPF. Here we report that fibrotic AT2 cells regulate production and crosslinking of ECM via the co-transcriptional activator YAP. YAP leads to increase expression of Lysyloxidase (LOX) and subsequent LOX mediated crosslinking by fibrotic AT2 cells. Pharmacological YAP inhibition reverses fibrotic AT2 cell reprogramming and LOX expression in experimental lung fibrosis in vivo and in human fibrotic tissue ex vivo . We thus identify YAP-TEAD/LOX inhibition in AT2 cells as a promising potential new therapy for IPF patients. In ; SnRNAseq analysis of PCLS treated with Verteporfin in fibrotic conditions Four PCLS slices per control donor (n=2) at day 5 after DMSO, FC, FC+Verteporfin stimulation were washed in cold 1X PBS and snap frozen. Nuclei were extracted using the Nuclei Isolation kit (CG000505, 10X Genomics,) Around 20’000 nuclei were loaded on a Chip G with Chromium Single Cell 3′ v3.1 gel beads and reagents (3′ GEX v3.1, 10x Genomics). Final libraries were analyzed on an Agilent Bioanalyzer High Sensitivity DNA chip for qualitative control purposes. cDNA libraries were sequenced on a HiSeq 4000 Illumina platform aiming for 150 million reads per library and a sequencing configuration of 26 base pair (bp) on read1 and 98 bp on read2.). Paired reads were filtered if either the cell barcode or unique molecular identifier (UMI) sequence had more than 1 bp with a phred of <20. Reads were aligned with STAR (v2.7.9a) to the human genome reference GRCh38 release 99 from ensemble. Collapsed UMIs with reads that span both exonic and intronic sequences were retained as both separate and combined gene expression assays. ; After preprocessing, analysis of the ex vivo human PCLS snRNA-seq data was conducted ...