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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 6

Expression of LYPD1, PRSS23, and CDH6 declines during podocyte maturation in organoids and human kidneys.

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Expression of LYPD1, PRSS23, and CDH6 declines during podocyte maturatio...
Columns demonstrating LYPD1 (left), PRSS23 (middle), and CDH6 (right) expression in A–C. (A) Feature plots of overlaid kidney organoid t-SNE plot from Figure 2C. Dashed lines outline cells in EGE cluster. (B) Overlaid podocyte (n = 645 transcriptomes) and PEC (n = 546 transcriptomes) lineage trajectories showing average expression of LYPD1, PRSS23, and CDH6; color key on far right. Gray shading, 95% CI. (C) Developing human kidney trajectories as described in ref. 32 representing 6,414 transcriptomes with overlaid gene expression of LYPD1, PRSS23, and CDH6 oriented for optimal visualization of podocyte lineage. Arrows, maximal podocyte lineage expression; arrowheads, nonpodocyte lineage maximal expression. PC, podocyte; S, stromal; NPG, nephron progenitor; CD, collecting duct; LOH, Loop of Henle; PT, proximal tubule. Color scales represent normalized log expression.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

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