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Basic Research
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Kidney Single-cell Transcriptomes Predict Spatial Corticomedullary Gene Expression and Tissue Osmolality Gradients

Christian Hinze, Nikos Karaiskos, Anastasiya Boltengagen, Katharina Walentin, Klea Redo, Nina Himmerkus, Markus Bleich, S. Steven Potter, Andrew S. Potter, Kai-Uwe Eckardt, Christine Kocks, Nikolaus Rajewsky and Kai M. Schmidt-Ott
JASN February 2021, 32 (2) 291-306; DOI: https://doi.org/10.1681/ASN.2020070930
Christian Hinze
1Department of Nephrology and Medical Intensive Care, Charité – Universitätsmedizin, Berlin, Germany
2Molecular and Translational Kidney Research, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
3Berlin Institute of Health, Berlin, Germany
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Nikos Karaiskos
4Systems Biology of Gene Regulatory Elements, Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
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Anastasiya Boltengagen
4Systems Biology of Gene Regulatory Elements, Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
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Katharina Walentin
2Molecular and Translational Kidney Research, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
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Klea Redo
1Department of Nephrology and Medical Intensive Care, Charité – Universitätsmedizin, Berlin, Germany
2Molecular and Translational Kidney Research, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
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Nina Himmerkus
5Department of Physiology, Physiology of Membrane Transport, Christian-Albrechts-Universität, Kiel, Germany
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Markus Bleich
5Department of Physiology, Physiology of Membrane Transport, Christian-Albrechts-Universität, Kiel, Germany
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S. Steven Potter
6Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
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Andrew S. Potter
6Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
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Kai-Uwe Eckardt
1Department of Nephrology and Medical Intensive Care, Charité – Universitätsmedizin, Berlin, Germany
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Christine Kocks
4Systems Biology of Gene Regulatory Elements, Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
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Nikolaus Rajewsky
4Systems Biology of Gene Regulatory Elements, Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
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Kai M. Schmidt-Ott
1Department of Nephrology and Medical Intensive Care, Charité – Universitätsmedizin, Berlin, Germany
2Molecular and Translational Kidney Research, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
3Berlin Institute of Health, Berlin, Germany
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Significance Statement

Single-cell transcriptomes from dissociated tissues provide insights into cell type composition and gene expression, but spatial positional information is lost during tissue dissociation. Computational deconvolution of the spatial position of kidney tubule cells from whole kidney single-cell transcriptomes and reconstructed spatial and cell type–specific gene-expression patterns, from the cortex to medulla, revealed gradual changes that follow the physiological corticomedullary gradient of tissue osmolality. Quantification of osmo-responsive gene expression detected in single-cell transcriptomes identified flattened expression gradients in mice, with a genetically induced defect of medullary osmolyte retention. Hence, single-cell transcriptomes harbor previously underappreciated information on spatial gene expression and regional cellular states.

Abstract

Background Single-cell transcriptomes from dissociated tissues provide insights into cell types and their gene expression and may harbor additional information on spatial position and the local microenvironment. The kidney’s cells are embedded into a gradient of increasing tissue osmolality from the cortex to the medulla, which may alter their transcriptomes and provide cues for spatial reconstruction.

Methods Single-cell or single-nuclei mRNA sequencing of dissociated mouse kidneys and of dissected cortex, outer, and inner medulla, to represent the corticomedullary axis, was performed. Computational approaches predicted the spatial ordering of cells along the corticomedullary axis and quantitated expression levels of osmo-responsive genes. In situ hybridization validated computational predictions of spatial gene-expression patterns. The strategy was used to compare single-cell transcriptomes from wild-type mice to those of mice with a collecting duct–specific knockout of the transcription factor grainyhead-like 2 (Grhl2CD−/−), which display reduced renal medullary osmolality.

Results Single-cell transcriptomics from dissociated kidneys provided sufficient information to approximately reconstruct the spatial position of kidney tubule cells and to predict corticomedullary gene expression. Spatial gene expression in the kidney changes gradually and osmo-responsive genes follow the physiologic corticomedullary gradient of tissue osmolality. Single-nuclei transcriptomes from Grhl2CD−/− mice indicated a flattened expression gradient of osmo-responsive genes compared with control mice, consistent with their physiologic phenotype.

Conclusions Single-cell transcriptomics from dissociated kidneys facilitated the prediction of spatial gene expression along the corticomedullary axis and quantitation of osmotically regulated genes, allowing the prediction of a physiologic phenotype.

  • microenvironment
  • spatial resolution single-cell transcriptomics
  • osmolality gradient
  • osmogenes
  • cell types
  • Copyright © 2021 by the American Society of Nephrology
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Journal of the American Society of Nephrology: 32 (2)
Journal of the American Society of Nephrology
Vol. 32, Issue 2
February 2021
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Kidney Single-cell Transcriptomes Predict Spatial Corticomedullary Gene Expression and Tissue Osmolality Gradients
Christian Hinze, Nikos Karaiskos, Anastasiya Boltengagen, Katharina Walentin, Klea Redo, Nina Himmerkus, Markus Bleich, S. Steven Potter, Andrew S. Potter, Kai-Uwe Eckardt, Christine Kocks, Nikolaus Rajewsky, Kai M. Schmidt-Ott
JASN Feb 2021, 32 (2) 291-306; DOI: 10.1681/ASN.2020070930

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Kidney Single-cell Transcriptomes Predict Spatial Corticomedullary Gene Expression and Tissue Osmolality Gradients
Christian Hinze, Nikos Karaiskos, Anastasiya Boltengagen, Katharina Walentin, Klea Redo, Nina Himmerkus, Markus Bleich, S. Steven Potter, Andrew S. Potter, Kai-Uwe Eckardt, Christine Kocks, Nikolaus Rajewsky, Kai M. Schmidt-Ott
JASN Feb 2021, 32 (2) 291-306; DOI: 10.1681/ASN.2020070930
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Keywords

  • microenvironment
  • spatial resolution single-cell transcriptomics
  • osmolality gradient
  • osmogenes
  • cell types

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