Applying single-cell profiling to assess drug anti-fibrotic properties in the human precision-cut lung slice model of fibrosis

Here, we used human precision lung cut slices (PCLS) and single nuclear RNA sequencing (SnRNA-Seq) to determine the effect of several compounds targeting key fibrotic pathways and validating drugs predicted as anti-fibrotic. After 5 days of stimulation with DMSO, FC (TGFb, TNFa, PDGF and LPA), FC + treatment, PCLS were collected. Treatment included IPF FDA-approved drugs (Nintedanib), as well as drugs currently in clinical trials. Single nuclei suspensions were processed according to the 10x protocol. Ligand Receptor analysis was performed using Niches package. 250000 single nuclei transcriptomes were analyzed. Fibrotic cocktail stimulation induced the emergence of aberrant basaloid cells (Panel A). No treatment stimulation influenced cell type proportions (Panel B). Several treatments significantly affected the gene signature of fibroblast and aberrant basaloid cells signature, including Verteporfin, a drug targeting YAP-TEAD signaling (Panel C). In addition, preliminary and ongoing ligand-receptor analysis suggests treatment condition significantly modified cellular connectivity of the aberrant basal cells in particular with the alveolar epithelial cells, as compared to the fibrotic condition (Panel D). Applying SnRNA seq to PCLS treated with drugs is an innovative and promising model to assess and potentially predict drug efficacy in human tissues, at a cellular resolution <fig><object-id>erj;64/suppl_68/OA1896/F1</object-id><object-id>F1</object-id><object-id>F1</object-id><graphic></graphic></fig>