Organoid single cell profiling identifies a transcriptional signature of glomerular disease
Jennifer L. Harder, … , European Renal cDNA Bank (ERCB), Nephrotic Syndrome Study Network (NEPTUNE)
Jennifer L. Harder, … , European Renal cDNA Bank (ERCB), Nephrotic Syndrome Study Network (NEPTUNE)
Published January 10, 2019
Citation Information: JCI Insight. 2019;4(1):e122697. https://doi.org/10.1172/jci.insight.122697.
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Research Article Nephrology

Organoid single cell profiling identifies a transcriptional signature of glomerular disease

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.

Authors

Jennifer L. Harder, Rajasree Menon, Edgar A. Otto, Jian Zhou, Sean Eddy, Noel L. Wys, Christopher O’Connor, Jinghui Luo, Viji Nair, Cristina Cebrian, Jason R. Spence, Markus Bitzer, Olga G. Troyanskaya, Jeffrey B. Hodgin, Roger C. Wiggins, Benjamin S. Freedman, Matthias Kretzler, European Renal cDNA Bank (ERCB), Nephrotic Syndrome Study Network (NEPTUNE)

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Figure 7

Expression of candidate early glomerular epithelial/PEC genes correlates with chronic kidney disease.(A) Box plots comparing LYPD1 (top), PRSS23 (middle), and CDH6 (bottom) expression in CKD relative to LD, as in Table 1.

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Expression of candidate early glomerular epithelial/PEC genes correlates...
Whiskers represent the upper and lower adjacent values. (B) Scatter plots showing gene expression from A relative to eGFR in CKD and LD. Statistical significance calculated using Pearson correlation. (C) Box plots as in A comparing individual gene expression levels to proteinuria groups in lupus nephritis samples from ERCB in Nephroseq (www.nephroseq.org). Subnephrotic (Sub-N), n = 18; nephrotic, n = 9. Statistical significance calculated using 1-tailed t test. Whiskers represent the 10th/90th percentile values as precomputed within Nephroseq. FC, fold change. *P < 0.05. See Supplemental Figure 4.