Organoid single cell profiling identifies a transcriptional signature of glomerular disease.
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)
Author Information
Jennifer L Harder: Department of Internal Medicine, Division of Nephrology, and.
Rajasree Menon: Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Edgar A Otto: Department of Internal Medicine, Division of Nephrology, and.
Jian Zhou: Flatiron Institute, Simons Foundation, New York, New York, USA.
Sean Eddy: Department of Internal Medicine, Division of Nephrology, and.
Noel L Wys: Department of Internal Medicine, Division of Nephrology, and.
Christopher O'Connor: Department of Internal Medicine, Division of Nephrology, and.
Jinghui Luo: Department of Pathology and.
Viji Nair: Department of Internal Medicine, Division of Nephrology, and.
Cristina Cebrian: Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan, USA.
Jason R Spence: Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan, USA.
Markus Bitzer: Department of Internal Medicine, Division of Nephrology, and.
Olga G Troyanskaya: Flatiron Institute, Simons Foundation, New York, New York, USA.
Jeffrey B Hodgin: Department of Pathology and.
Roger C Wiggins: Department of Internal Medicine, Division of Nephrology, and.
Benjamin S Freedman: Department of Medicine, Division of Nephrology.
Matthias Kretzler: Department of Internal Medicine, Division of Nephrology, and.
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.
