Fig. 5: Proteome-based gene signature of TNFα activation in organoids identifies group of individuals with poorer clinical outcomes in proteinuric kidney disease.
From: An integrated organoid omics map extends modeling potential of kidney disease
a Schematic defining origins of Organoid and Tissue TNF gene signatures (left column) as well as Organoid TNF score (bottom middle column) used in this manuscript, with special attention to FSGS/MCD cohort with the NEPTUNE study (bottom left column) demonstrating poorer outcomes and higher TNF activity for individuals in cluster 3 as in Mariani et al. (2023); right column shows strategy for identifying potential biomarker candidates using Organoid TNF signature genes. b Z-scores showing summary expression of organoid TNF signature genes in human kidney diseases, generated from ERCB microarray data from microdissected human kidney biopsy tissue (boxplots for the 268 in ERCB of the total 322 genes assessed, Supplementary Data 10). Plots: median, boxes 25–75% percentile, whiskers represent the min. to max. values. Numbers of individual samples are indicated in parentheses. LD = Living Donor. Unpaired t test. c Venn diagram comparing gene sets of Organoid and Tissue TNF signatures (Fig. 4d, f, Supplementary Data 10). d Literature‐based network generated from the combination of Organoid and Tissue TNF signature genes (total 584). e, f box and whisker plots (white line, mean; box, 75%; whiskers, 90%) showing summary gene expression in diseased human kidney based on the Organoid TNF signature score in FSGS/MCD clusters (319 of the 322 genes detected) as in (a), and divided by proteins in organoid secretome (top, all 22 genes) and cell lysates (bottom, 299 of 302 genes); 2 proteins were expressed in both; ***p < 1.85 × 10E−11. Unequal variance two-tailed t test. g Dot plots of 10 TNF signature overlap gene expression from (c) in individuals with FSGS/MCD separated by TNFα activity status, generated from snRNA-seq data. h Dot plots of CXCL10 expression separated by diseased kidney TNFα activity status and cell type. Arrows highlight cell types of interest with higher expression in individuals with high TNFα status; cell type cluster names as in Supplementary Fig. 5C. a, c created using BioRender. Source data are provided as a Source Data file.
