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Decoding myofibroblast origins in human kidney fibrosis

Author

Listed:
  • Christoph Kuppe

    (RWTH Aachen University
    RWTH Aachen University)

  • Mahmoud M. Ibrahim

    (RWTH Aachen University
    RWTH Aachen University
    Bayer Pharma AG)

  • Jennifer Kranz

    (RWTH Aachen University
    St Antonius Hospital
    Martin-Luther-University)

  • Xiaoting Zhang

    (RWTH Aachen University)

  • Susanne Ziegler

    (RWTH Aachen University)

  • Javier Perales-Patón

    (RWTH Aachen University
    Institute for Computational Biomedicine, Faculty of Medicine, Heidelberg University and Heidelberg University Hospital, BioQuant
    RWTH Aachen University Hospital)

  • Jitske Jansen

    (RWTH Aachen University
    Radboud University Medical Center
    Radboud University Medical Center, Amalia Children’s Hospital)

  • Katharina C. Reimer

    (RWTH Aachen University
    RWTH Aachen University
    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
    RWTH Aachen University)

  • Yaoxian Xu

    (RWTH Aachen University)

  • Nazanin Kabgani

    (RWTH Aachen University)

  • Nadine Kaesler

    (RWTH Aachen University
    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
    Monash University)

  • Tobias B. Huber

    (University Medical Center Hamburg-Eppendorf)

  • Peter Boor

    (RWTH Aachen University
    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
    Erasmus MC Cancer Institute)

  • Julio Saez-Rodriguez

    (Institute for Computational Biomedicine, Faculty of Medicine, Heidelberg University and Heidelberg University Hospital, BioQuant
    RWTH Aachen University Hospital
    Heidelberg University)

  • Neil C. Henderson

    (University of Edinburgh
    University of Edinburgh)

  • Rafael Kramann

    (RWTH Aachen University
    RWTH Aachen University
    Nephrology and Transplantation, Erasmus Medical Center)

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.

Suggested Citation

  • 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-Kan, 2021. "Decoding myofibroblast origins in human kidney fibrosis," Nature, Nature, vol. 589(7841), pages 281-286, January.
  • Handle: RePEc:nat:nature:v:589:y:2021:i:7841:d:10.1038_s41586-020-2941-1
    DOI: 10.1038/s41586-020-2941-1
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    Citations

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    Cited by:

    1. Haojia Wu & Eryn E. Dixon & Qiao Xuanyuan & Juanru Guo & Yasuhiro Yoshimura & Chitnis Debashish & Anezka Niesnerova & Hao Xu & Morgane Rouault & Benjamin D. Humphreys, 2024. "High resolution spatial profiling of kidney injury and repair using RNA hybridization-based in situ sequencing," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    2. Shirong Cao & Yu Pan & Andrew S. Terker & Juan Pablo Arroyo Ornelas & Yinqiu Wang & Jiaqi Tang & Aolei Niu & Sarah Abu Kar & Mengdi Jiang & Wentian Luo & Xinyu Dong & Xiaofeng Fan & Suwan Wang & Matth, 2023. "Epidermal growth factor receptor activation is essential for kidney fibrosis development," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    3. Merve Kayhan & Judith Vouillamoz & Daymé Gonzalez Rodriguez & Milica Bugarski & Yasutaka Mitamura & Julia Gschwend & Christoph Schneider & Andrew Hall & David Legouis & Cezmi A. Akdis & Leary Peter & , 2023. "Intrinsic TGF-β signaling attenuates proximal tubule mitochondrial injury and inflammation in chronic kidney disease," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    4. LiangYu Zhao & Sha Han & HengChuan Su & JianYing Li & ErLei Zhi & Peng Li & ChenCheng Yao & RuHui Tian & HuiXing Chen & HuiRong Chen & JiaQiang Luo & ChenKun Shi & ZhiYong Ji & JianLin Hu & Gang Wu & , 2022. "Single-cell transcriptome atlas of the human corpus cavernosum," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    5. Jasim Kada Benotmane & Jan Kueckelhaus & Paulina Will & Junyi Zhang & Vidhya M. Ravi & Kevin Joseph & Roman Sankowski & Jürgen Beck & Catalina Lee-Chang & Oliver Schnell & Dieter Henrik Heiland, 2023. "High-sensitive spatially resolved T cell receptor sequencing with SPTCR-seq," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    6. Marie Bobowski-Gerard & Clémence Boulet & Francesco P. Zummo & Julie Dubois-Chevalier & Céline Gheeraert & Mohamed Bou Saleh & Jean-Marc Strub & Amaury Farce & Maheul Ploton & Loïc Guille & Jimmy Vand, 2022. "Functional genomics uncovers the transcription factor BNC2 as required for myofibroblastic activation in fibrosis," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    7. Urban Lendahl & Lars Muhl & Christer Betsholtz, 2022. "Identification, discrimination and heterogeneity of fibroblasts," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

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