Abstract

To study disease development, an inventory of an organ's cell types and understanding of physiologic function is paramount. Here, we performed single-cell RNA sequencing to examine heterogeneity of murine pancreatic duct cells, pancreatobiliary cells, and intrapancreatic bile duct cells. We describe an epithelial-mesenchymal transitory axis in our three pancreatic duct subpopulations and identify osteopontin as a regulator of this fate decision as well as human duct cell dedifferentiation. Our results further identify functional heterogeneity within pancreatic duct subpopulations by elucidating a role for geminin in accumulation of DNA damage in the setting of chronic pancreatitis. Our findings implicate diverse functional roles for subpopulations of pancreatic duct cells in maintenance of duct cell identity and disease progression and establish a comprehensive road map of murine pancreatic duct cell, pancreatobiliary cell, and intrapancreatic bile duct cell homeostasis.

Data availability

Sequencing data have been deposited in GEO under accession code GSE159343.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Audrey Marie Hendley

    University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Arjun Arkal Rao

    University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Laura Leonhardt

    University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Sudipta Ashe

    University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Jennifer A Smith

    University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Simone Giacometti

    University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Xianlu L Peng

    University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Honglin Jiang

    University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. David Berrios

    University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Mathias Pawlak

    N/A, BlueRock Therapeutics, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Lucia Y Li

    University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Jonghyun Lee

    University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Eric A Collisson

    University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8037-9388
  14. Mark S Anderson

    University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3093-4758
  15. Gabriela K Fragiadakis

    University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Jen Jen Yeh

    University of North Carolina Chapel Hill, Chapel Hill, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Jimmie Ye Chun

    University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  18. Grace E Kim

    University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  19. Valerie M Weaver

    University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  20. Matthias Hebrok

    University of California, San Francisco, San Francisco, United States
    For correspondence
    Matthias.Hebrok@ucsf.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3833-8862

Funding

National Cancer Institute (F32 CA221114)

  • Audrey Marie Hendley

Hirshberg Foundation for Pancreatic Cancer Research (Seed Grant)

  • Audrey Marie Hendley

National Cancer Institute (R01 CA222862)

  • Eric A Collisson

National Cancer Institute (R01 CA172045)

  • Matthias Hebrok

Parker Institute for Cancer Immunotherapy (PICI Opportunity Grant)

  • Matthias Hebrok

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Lori Sussel, University of Colorado Anschutz Medical Campus, United States

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (AN170192) of the University of California San Francisco.

Version history

  1. Received: February 23, 2021
  2. Accepted: May 18, 2021
  3. Accepted Manuscript published: May 19, 2021 (version 1)
  4. Version of Record published: June 7, 2021 (version 2)

Copyright

© 2021, Hendley et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Audrey Marie Hendley
  2. Arjun Arkal Rao
  3. Laura Leonhardt
  4. Sudipta Ashe
  5. Jennifer A Smith
  6. Simone Giacometti
  7. Xianlu L Peng
  8. Honglin Jiang
  9. David Berrios
  10. Mathias Pawlak
  11. Lucia Y Li
  12. Jonghyun Lee
  13. Eric A Collisson
  14. Mark S Anderson
  15. Gabriela K Fragiadakis
  16. Jen Jen Yeh
  17. Jimmie Ye Chun
  18. Grace E Kim
  19. Valerie M Weaver
  20. Matthias Hebrok
(2021)
Single cell transcriptome analysis defines heterogeneity of the murine pancreatic ductal tree
eLife 10:e67776.
https://doi.org/10.7554/eLife.67776

Share this article

https://doi.org/10.7554/eLife.67776

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