Decoding myofibroblast origins in human kidney fibrosis

Christoph Kuppe, Mahmoud M. Ibrahim, Jennifer Kranz, Xiaoting Zhang, Susanne Ziegler, Javier Perales-Patón, Jitske Jansen, Katharina C. Reimer, James R. Smith, Ross Dobie, John R. Wilson-Kanamori, Maurice Halder, Yaoxian Xu, Nazanin Kabgani, Nadine Kaesler, Martin Klaus, Lukas Gernhold, Victor G. Puelles, Tobias B. Huber, Peter Boor, Sylvia Menzel, Remco M. Hoogenboezem, Eric M. J. Bindels, Joachim Steffens, Jürgen Floege, Rebekka K. Schneider, Julio Saez-Rodriguez, Neil C. Henderson and Rafael Kramann ()
Additional contact information
Christoph Kuppe: RWTH Aachen University
Mahmoud M. Ibrahim: RWTH Aachen University
Jennifer Kranz: RWTH Aachen University
Xiaoting Zhang: RWTH Aachen University
Susanne Ziegler: RWTH Aachen University
Javier Perales-Patón: RWTH Aachen University
Jitske Jansen: RWTH Aachen University
Katharina C. Reimer: RWTH Aachen University
James R. Smith: University of Edinburgh
Ross Dobie: University of Edinburgh
John R. Wilson-Kanamori: University of Edinburgh
Maurice Halder: RWTH Aachen University
Yaoxian Xu: RWTH Aachen University
Nazanin Kabgani: RWTH Aachen University
Nadine Kaesler: RWTH Aachen University
Martin Klaus: University Medical Center Hamburg-Eppendorf
Lukas Gernhold: University Medical Center Hamburg-Eppendorf
Victor G. Puelles: University Medical Center Hamburg-Eppendorf
Tobias B. Huber: University Medical Center Hamburg-Eppendorf
Peter Boor: RWTH Aachen University
Sylvia Menzel: RWTH Aachen University
Remco M. Hoogenboezem: Erasmus MC Cancer Institute
Eric M. J. Bindels: Erasmus MC Cancer Institute
Joachim Steffens: St Antonius Hospital
Jürgen Floege: RWTH Aachen University
Rebekka K. Schneider: RWTH Aachen University
Julio Saez-Rodriguez: Institute for Computational Biomedicine, Faculty of Medicine, Heidelberg University and Heidelberg University Hospital, BioQuant
Neil C. Henderson: University of Edinburgh
Rafael Kramann: RWTH Aachen University

Nature, 2021, vol. 589, issue 7841, 281-286

Abstract: Abstract Kidney fibrosis is the hallmark of chronic kidney disease progression; however, at present no antifibrotic therapies exist1–3. The origin, functional heterogeneity and regulation of scar-forming cells that occur during human kidney fibrosis remain poorly understood1,2,4. Here, using single-cell RNA sequencing, we profiled the transcriptomes of cells from the proximal and non-proximal tubules of healthy and fibrotic human kidneys to map the entire human kidney. This analysis enabled us to map all matrix-producing cells at high resolution, and to identify distinct subpopulations of pericytes and fibroblasts as the main cellular sources of scar-forming myofibroblasts during human kidney fibrosis. We used genetic fate-tracing, time-course single-cell RNA sequencing and ATAC–seq (assay for transposase-accessible chromatin using sequencing) experiments in mice, and spatial transcriptomics in human kidney fibrosis, to shed light on the cellular origins and differentiation of human kidney myofibroblasts and their precursors at high resolution. Finally, we used this strategy to detect potential therapeutic targets, and identified NKD2 as a myofibroblast-specific target in human kidney fibrosis.

Date: 2021
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DOI: 10.1038/s41586-020-2941-1

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