Organoid single cell profiling identifies a transcriptional signature of glomerular disease. Author Jennifer Harder, Rajasree Menon, Edgar Otto, Jian Zhou, Sean Eddy, Noel Wys, Christopher O'Connor, Jinghui Luo, Viji Nair, Cristina Cebrian, Jason Spence, Markus Bitzer, Olga Troyanskaya, Jeffrey Hodgin, Roger Wiggins, Benjamin Freedman, Matthias Kretzler, European Renal cDNA Bank (ERCB), Nephrotic Syndrome Study Network (NEPTUNE) Publication Year 2019 Type Journal Article Abstract Podocyte injury is central to many forms of kidney disease, but transcriptional signatures reflecting podocyte injury and compensation mechanisms are challenging to analyze in vivo. Human kidney organoids derived from pluripotent stem cells (PSCs), a potentially new model for disease and regeneration, present an opportunity to explore the transcriptional plasticity of podocytes. Here, transcriptional profiling of more than 12,000 single cells from human PSC-derived kidney organoid cultures was used to identify robust and reproducible cell lineage gene expression signatures shared with developing human kidneys based on trajectory analysis. Surprisingly, the gene expression signature characteristic of developing glomerular epithelial cells was also observed in glomerular tissue from a kidney disease cohort. This signature correlated with proteinuria and inverse eGFR, and it was confirmed in an independent podocytopathy cohort. Three genes in particular were further characterized as potentially novel components of the glomerular disease signature. We conclude that cells in human PSC-derived kidney organoids reliably recapitulate the developmental transcriptional program of podocytes and other cell lineages in the human kidney and that transcriptional profiles seen in developing podocytes are reactivated in glomerular disease. Our findings demonstrate an approach to identifying potentially novel molecular programs involved in the pathogenesis of glomerulopathies. Keywords Humans, Adult, Single-Cell Analysis, Transcriptome, Organoids, Pluripotent Stem Cells, Tissue Culture Techniques, Embryonic Stem Cells, Kidney Diseases, Kidney Glomerulus, Podocytes Journal JCI Insight Volume 4 Issue 1 Date Published 2019 Jan 10 ISSN Number 2379-3708 DOI 10.1172/jci.insight.122697 Alternate Journal JCI Insight PMCID PMC6485369 PMID 30626756 PubMedPubMed CentralGoogle ScholarBibTeXEndNote X3 XML