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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

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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 3

Cells of kidney organoids share the same cell type–specific transcriptional trajectories as developing human kidney.

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Cells of kidney organoids share the same cell type–specific transcriptio...
(A) Correlation matrix comparing gene expression profiles of cells in clusters from organoids (whole well) to developing human kidney of estimated gestation days 105–115. The intensity of the overall image was adjusted to maximize the discernable visible range of Z score intensities, color indicates correlation (red, positive; blue, negative). (B) Overlaid trajectory analyses of combined single cell transcriptomes from developing human kidneys, whole well organoid cultures, and isolated organoids. N, cumulative number of transcriptomes used in trajectory analysis, and n, contributing number of transcriptomes from each dataset. See related Supplemental Video 1. (C) Trajectory segment cell type assignment of developing kidney and organoids based on gene expression patterns as in Supplemental Figure 2B. (D) Superimposed t-SNE cluster cell type assignments of selected kidney clusters from whole well organoids only (see Figure 2C) overlaid on cell lineage trajectory. Cells from all other clusters are represented in gray. See related Supplemental Figure 2.

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