Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

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

View ORCID ProfileYoshiharu Muto, View ORCID ProfileEryn E. Dixon, View ORCID ProfileYasuhiro Yoshimura, View ORCID ProfileHaojia Wu, View ORCID ProfileKohei Omachi, Andrew J. King, Eric N. Olson, Marvin G. Gunawan, View ORCID ProfileJay J. Kuo, Jennifer Cox, View ORCID ProfileJeffrey H. Miner, View ORCID ProfileStephen L. Seliger, View ORCID ProfileOwen M. Woodward, View ORCID ProfilePaul A. Welling, View ORCID ProfileTerry J. Watnick, View ORCID ProfileBenjamin D. Humphreys
doi: https://doi.org/10.1101/2021.10.21.465323
Yoshiharu Muto
1Division of Nephrology, Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Yoshiharu Muto
Eryn E. Dixon
1Division of Nephrology, Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Eryn E. Dixon
Yasuhiro Yoshimura
1Division of Nephrology, Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Yasuhiro Yoshimura
Haojia Wu
1Division of Nephrology, Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Haojia Wu
Kohei Omachi
1Division of Nephrology, Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Kohei Omachi
Andrew J. King
2Chinook Therapeutics, Inc., Seattle, WA and Vancouver, BC, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Eric N. Olson
2Chinook Therapeutics, Inc., Seattle, WA and Vancouver, BC, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Marvin G. Gunawan
2Chinook Therapeutics, Inc., Seattle, WA and Vancouver, BC, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jay J. Kuo
2Chinook Therapeutics, Inc., Seattle, WA and Vancouver, BC, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Jay J. Kuo
Jennifer Cox
2Chinook Therapeutics, Inc., Seattle, WA and Vancouver, BC, Canada
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jeffrey H. Miner
1Division of Nephrology, Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Jeffrey H. Miner
Stephen L. Seliger
3Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Stephen L. Seliger
Owen M. Woodward
4Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Owen M. Woodward
Paul A. Welling
5Johns Hopkins School of Medicine, Baltimore, MD, United States
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Paul A. Welling
Terry J. Watnick
3Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Terry J. Watnick
Benjamin D. Humphreys
1Division of Nephrology, Department of Medicine, Washington University in St. Louis, St. Louis, MO, USA
6Department of Developmental Biology, Washington University in St. Louis, St. Louis, MO, USA
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Benjamin D. Humphreys
  • For correspondence: humphreysbd@wustl.edu
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Supplementary material
  • Preview PDF
Loading

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is the leading genetic cause of end stage renal disease and is characterized by the formation and progressive expansion of kidney cysts. Most ADPKD cases arise from mutations in either the PKD1 or PKD2 gene but the precise downstream signaling pathways driving cyst growth are not well understood, and relatively few studies investigate human cystic kidney due to sample scarcity. In order to better understand the cell types and states driving human ADPKD progression, we analyzed eight ADPKD and five healthy human kidney samples, generating a single cell multiomic atlas consisting of ~100,000 single nucleus transcriptomes and ~50,000 single nucleus epigenomes. The integrated datasets identified 11 primary cell clusters including most epithelial cell types as well as large endothelial and fibroblast cell clusters. Proximal tubular cells from ADPKD kidneys expressed a failed repair transcriptomic signature characterized by profibrotic and proinflammatory transcripts. We identified the G protein-coupled receptor GPRC5A as specifically upregulated in cyst lining cells derived from collecting duct. The principal cell subpopulation enriched for GPRC5A expression also exhibited increased transcription factor binding motif availability for NF-κB, TEAD, CREB and retinoic acid receptor families and we identified and validated a distal enhancer regulating GPRC5A expression containing these transcription factor binding motifs. This study establishes the single cell transcriptomic and epigenomic landscape of ADPKD, revealing previously unrecognized cellular heterogeneity.

Competing Interest Statement

B.D.H. is a consultant for Janssen Research & Development, LLC, Pfizer and Chinook Therapeutics, holds equity in Chinook Therapeutics and grant funding from Chinook Therapeutics and Janssen Research & Development, LLC. O.M.W has received grants from AstraZeneca unrelated to the current work. J.H.M. has received funding from Chinook Therapeutics unrelated to the current work. S.S. has received grant funding from Otsuka, Palladio Biosciences, Kadmon Corporation, Sanofi, and Reata Pharmaceuticals. A.J.K., E.O., M.G., J.K. and J.C. are employees and stock holders of Chinook Therapeutics.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
Back to top
PreviousNext
Posted October 22, 2021.
Download PDF

Supplementary Material

Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
Defining cellular complexity in human autosomal dominant polycystic kidney disease by multimodal single cell analysis
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
Defining cellular complexity in human autosomal dominant polycystic kidney disease by multimodal single cell analysis
Yoshiharu Muto, Eryn E. Dixon, Yasuhiro Yoshimura, Haojia Wu, Kohei Omachi, Andrew J. King, Eric N. Olson, Marvin G. Gunawan, Jay J. Kuo, Jennifer Cox, Jeffrey H. Miner, Stephen L. Seliger, Owen M. Woodward, Paul A. Welling, Terry J. Watnick, Benjamin D. Humphreys
bioRxiv 2021.10.21.465323; doi: https://doi.org/10.1101/2021.10.21.465323
Digg logo Reddit logo Twitter logo Facebook logo Google logo LinkedIn logo Mendeley logo
Citation Tools
Defining cellular complexity in human autosomal dominant polycystic kidney disease by multimodal single cell analysis
Yoshiharu Muto, Eryn E. Dixon, Yasuhiro Yoshimura, Haojia Wu, Kohei Omachi, Andrew J. King, Eric N. Olson, Marvin G. Gunawan, Jay J. Kuo, Jennifer Cox, Jeffrey H. Miner, Stephen L. Seliger, Owen M. Woodward, Paul A. Welling, Terry J. Watnick, Benjamin D. Humphreys
bioRxiv 2021.10.21.465323; doi: https://doi.org/10.1101/2021.10.21.465323

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Genomics
Subject Areas
All Articles
  • Animal Behavior and Cognition (4113)
  • Biochemistry (8815)
  • Bioengineering (6519)
  • Bioinformatics (23462)
  • Biophysics (11789)
  • Cancer Biology (9209)
  • Cell Biology (13322)
  • Clinical Trials (138)
  • Developmental Biology (7436)
  • Ecology (11409)
  • Epidemiology (2066)
  • Evolutionary Biology (15150)
  • Genetics (10436)
  • Genomics (14043)
  • Immunology (9171)
  • Microbiology (22154)
  • Molecular Biology (8812)
  • Neuroscience (47569)
  • Paleontology (350)
  • Pathology (1428)
  • Pharmacology and Toxicology (2491)
  • Physiology (3730)
  • Plant Biology (8080)
  • Scientific Communication and Education (1437)
  • Synthetic Biology (2221)
  • Systems Biology (6037)
  • Zoology (1253)