IDEAS home Printed from https://ideas.repec.org/a/nat/nature/v586y2020i7828d10.1038_s41586-020-2776-9.html
   My bibliography  Save this article

Phenotypic landscape of intestinal organoid regeneration

Author

Listed:
  • Ilya Lukonin

    (Friedrich Miescher Institute for Biomedical Research (FMI)
    University of Basel)

  • Denise Serra

    (Friedrich Miescher Institute for Biomedical Research (FMI)
    University of Basel)

  • Ludivine Challet Meylan

    (Friedrich Miescher Institute for Biomedical Research (FMI))

  • Katrin Volkmann

    (Friedrich Miescher Institute for Biomedical Research (FMI))

  • Janine Baaten

    (Genomics Institute of the Novartis Research Foundation)

  • Rui Zhao

    (Genomics Institute of the Novartis Research Foundation)

  • Shelly Meeusen

    (Genomics Institute of the Novartis Research Foundation)

  • Karyn Colman

    (Genomics Institute of the Novartis Research Foundation)

  • Francisca Maurer

    (Friedrich Miescher Institute for Biomedical Research (FMI))

  • Michael B. Stadler

    (Friedrich Miescher Institute for Biomedical Research (FMI)
    Swiss Institute of Bioinformatics)

  • Jeremy Jenkins

    (Novartis Institutes for Biomedical Research Chemical Biology and Therapeutics (CBT))

  • Prisca Liberali

    (Friedrich Miescher Institute for Biomedical Research (FMI)
    University of Basel)

Abstract

The development of intestinal organoids from single adult intestinal stem cells in vitro recapitulates the regenerative capacity of the intestinal epithelium1,2. Here we unravel the mechanisms that orchestrate both organoid formation and the regeneration of intestinal tissue, using an image-based screen to assay an annotated library of compounds. We generate multivariate feature profiles for hundreds of thousands of organoids to quantitatively describe their phenotypic landscape. We then use these phenotypic fingerprints to infer regulatory genetic interactions, establishing a new approach to the mapping of genetic interactions in an emergent system. This allows us to identify genes that regulate cell-fate transitions and maintain the balance between regeneration and homeostasis, unravelling previously unknown roles for several pathways, among them retinoic acid signalling. We then characterize a crucial role for retinoic acid nuclear receptors in controlling exit from the regenerative state and driving enterocyte differentiation. By combining quantitative imaging with RNA sequencing, we show the role of endogenous retinoic acid metabolism in initiating transcriptional programs that guide the cell-fate transitions of intestinal epithelium, and we identify an inhibitor of the retinoid X receptor that improves intestinal regeneration in vivo.

Suggested Citation

  • Ilya Lukonin & Denise Serra & Ludivine Challet Meylan & Katrin Volkmann & Janine Baaten & Rui Zhao & Shelly Meeusen & Karyn Colman & Francisca Maurer & Michael B. Stadler & Jeremy Jenkins & Prisca Lib, 2020. "Phenotypic landscape of intestinal organoid regeneration," Nature, Nature, vol. 586(7828), pages 275-280, October.
    • Handle: RePEc:nat:nature:v:586:y:2020:i:7828:d:10.1038_s41586-020-2776-9
    DOI: 10.1038/s41586-020-2776-9
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41586-020-2776-9
    File Function: Abstract
    Download Restriction: Access to the full text of the articles in this series is restricted.
    File URL: https://libkey.io/10.1038/s41586-020-2776-9?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    As the access to this document is restricted, you may want to search for a different version of it.

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Jina Yun & Simon Hansen & Otto Morris & David T. Madden & Clare Peters Libeu & Arjun J. Kumar & Cameron Wehrfritz & Aaron H. Nile & Yingnan Zhang & Lijuan Zhou & Yuxin Liang & Zora Modrusan & Michelle, 2023. "Senescent cells perturb intestinal stem cell differentiation through Ptk7 induced noncanonical Wnt and YAP signaling," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    2. Sara M. Parigi & Ludvig Larsson & Srustidhar Das & Ricardo O. Ramirez Flores & Annika Frede & Kumar P. Tripathi & Oscar E. Diaz & Katja Selin & Rodrigo A. Morales & Xinxin Luo & Gustavo Monasterio & C, 2022. "The spatial transcriptomic landscape of the healing mouse intestine following damage," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    3. Johannes Betge & Niklas Rindtorff & Jan Sauer & Benedikt Rauscher & Clara Dingert & Haristi Gaitantzi & Frank Herweck & Kauthar Srour-Mhanna & Thilo Miersch & Erica Valentini & Kim E. Boonekamp & Vero, 2022. "The drug-induced phenotypic landscape of colorectal cancer organoids," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    4. Gustavo Medeiros & Raphael Ortiz & Petr Strnad & Andrea Boni & Franziska Moos & Nicole Repina & Ludivine Challet Meylan & Francisca Maurer & Prisca Liberali, 2022. "Multiscale light-sheet organoid imaging framework," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    5. Yi Liu & Efren Reyes & David Castillo-Azofeifa & Ophir D. Klein & Todd Nystul & Diane L. Barber, 2023. "Intracellular pH dynamics regulates intestinal stem cell lineage specification," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    6. Ozren Stojanović & Jordi Altirriba & Dorothée Rigo & Martina Spiljar & Emilien Evrard & Benedek Roska & Salvatore Fabbiano & Nicola Zamboni & Pierre Maechler & Françoise Rohner-Jeanrenaud & Mirko Traj, 2021. "Dietary excess regulates absorption and surface of gut epithelium through intestinal PPARα," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    7. Kathleen Shah & Muralidhara Rao Maradana & M. Joaquina Delàs & Amina Metidji & Frederike Graelmann & Miriam Llorian & Probir Chakravarty & Ying Li & Mauro Tolaini & Michael Shapiro & Gavin Kelly & Chr, 2022. "Cell-intrinsic Aryl Hydrocarbon Receptor signalling is required for the resolution of injury-induced colonic stem cells," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    8. Eva C. Freckmann & Emma Sandilands & Erin Cumming & Matthew Neilson & Alvaro Román-Fernández & Konstantina Nikolatou & Marisa Nacke & Tamsin R. M. Lannagan & Ann Hedley & David Strachan & Mark Salji &, 2022. "Traject3d allows label-free identification of distinct co-occurring phenotypes within 3D culture by live imaging," Nature Communications, Nature, vol. 13(1), pages 1-21, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:nature:v:586:y:2020:i:7828:d:10.1038_s41586-020-2776-9. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.