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Defining cellular complexity in human autosomal dominant polycystic kidney disease by multimodal single cell analysis

Author

Listed:
  • Yoshiharu Muto

    (Washington University in St. Louis)

  • Eryn E. Dixon

    (Washington University in St. Louis)

  • Yasuhiro Yoshimura

    (Washington University in St. Louis)

  • Haojia Wu

    (Washington University in St. Louis)

  • Kohei Omachi

    (Washington University in St. Louis)

  • Nicolas Ledru

    (Washington University in St. Louis)

  • Parker C. Wilson

    (Washington University in St. Louis)

  • Andrew J. King

    (Chinook Therapeutics, Inc.)

  • N. Eric Olson

    (Chinook Therapeutics, Inc.)

  • Marvin G. Gunawan

    (Chinook Therapeutics, Inc.)

  • Jay J. Kuo

    (Chinook Therapeutics, Inc.)

  • Jennifer H. Cox

    (Chinook Therapeutics, Inc.)

  • Jeffrey H. Miner

    (Washington University in St. Louis)

  • Stephen L. Seliger

    (University of Maryland School of Medicine)

  • Owen M. Woodward

    (University of Maryland School of Medicine)

  • Paul A. Welling

    (Johns Hopkins School of Medicine)

  • Terry J. Watnick

    (University of Maryland School of Medicine)

  • Benjamin D. Humphreys

    (Washington University in St. Louis
    Washington University in St. Louis)

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is the leading genetic cause of end stage renal disease characterized by progressive expansion of kidney cysts. To better understand the cell types and states driving ADPKD progression, we analyze eight ADPKD and five healthy human kidney samples, generating single cell multiomic atlas consisting of ~100,000 single nucleus transcriptomes and ~50,000 single nucleus epigenomes. Activation of proinflammatory, profibrotic signaling pathways are driven by proximal tubular cells with a failed repair transcriptomic signature, proinflammatory fibroblasts and collecting duct cells. We identify GPRC5A as a marker for cyst-lining collecting duct cells that exhibits increased transcription factor binding motif availability for NF-κB, TEAD, CREB and retinoic acid receptors. We identify and validate a distal enhancer regulating GPRC5A expression containing these motifs. This single cell multiomic analysis of human ADPKD reveals previously unrecognized cellular heterogeneity and provides a foundation to develop better diagnostic and therapeutic approaches.

Suggested Citation

  • Yoshiharu Muto & Eryn E. Dixon & Yasuhiro Yoshimura & Haojia Wu & Kohei Omachi & Nicolas Ledru & Parker C. Wilson & Andrew J. King & N. Eric Olson & Marvin G. Gunawan & Jay J. Kuo & Jennifer H. Cox & , 2022. "Defining cellular complexity in human autosomal dominant polycystic kidney disease by multimodal single cell analysis," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34255-z
    DOI: 10.1038/s41467-022-34255-z
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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. Nicolas Ledru & Parker C. Wilson & Yoshiharu Muto & Yasuhiro Yoshimura & Haojia Wu & Dian Li & Amish Asthana & Stefan G. Tullius & Sushrut S. Waikar & Giuseppe Orlando & Benjamin D. Humphreys, 2024. "Predicting proximal tubule failed repair drivers through regularized regression analysis of single cell multiomic sequencing," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    3. Camille Cohen & Rana Mhaidly & Hugo Croizer & Yann Kieffer & Renaud Leclere & Anne Vincent-Salomon & Catherine Robley & Dany Anglicheau & Marion Rabant & Aurélie Sannier & Marc-Olivier Timsit & Sean E, 2024. "WNT-dependent interaction between inflammatory fibroblasts and FOLR2+ macrophages promotes fibrosis in chronic kidney disease," Nature Communications, Nature, vol. 15(1), pages 1-23, December.

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