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Parasitic helminths induce fetal-like reversion in the intestinal stem cell niche

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  • Ysbrand M. Nusse

    (Biomedical Sciences Graduate Program, University of California
    University of California)

  • Adam K. Savage

    (University of California)

  • Pauline Marangoni

    (University of California)

  • Axel K. M. Rosendahl-Huber

    (University of California)

  • Tyler A. Landman

    (University of California)

  • Frederic J. Sauvage

    (Genentech Inc.)

  • Richard M. Locksley

    (University of California)

  • Ophir D. Klein

    (University of California
    University of California)

Abstract

Epithelial surfaces form critical barriers to the outside world and are continuously renewed by adult stem cells1. Whereas dynamics of epithelial stem cells during homeostasis are increasingly well understood, how stem cells are redirected from a tissue-maintenance program to initiate repair after injury remains unclear. Here we examined infection by Heligmosomoides polygyrus, a co-evolved pathosymbiont of mice, to assess the epithelial response to disruption of the mucosal barrier. H. polygyrus disrupts tissue integrity by penetrating the duodenal mucosa, where it develops while surrounded by a multicellular granulomatous infiltrate2. Crypts overlying larvae-associated granulomas did not express intestinal stem cell markers, including Lgr53, in spite of continued epithelial proliferation. Granuloma-associated Lgr5− crypt epithelium activated an interferon-gamma (IFN-γ)-dependent transcriptional program, highlighted by Sca-1 expression, and IFN-γ-producing immune cells were found in granulomas. A similar epithelial response accompanied systemic activation of immune cells, intestinal irradiation, or ablation of Lgr5+ intestinal stem cells. When cultured in vitro, granuloma-associated crypt cells formed spheroids similar to those formed by fetal epithelium, and a sub-population of H. polygyrus-induced cells activated a fetal-like transcriptional program, demonstrating that adult intestinal tissues can repurpose aspects of fetal development. Therefore, re-initiation of the developmental program represents a fundamental mechanism by which the intestinal crypt can remodel itself to sustain function after injury.

Suggested Citation

  • Ysbrand M. Nusse & Adam K. Savage & Pauline Marangoni & Axel K. M. Rosendahl-Huber & Tyler A. Landman & Frederic J. Sauvage & Richard M. Locksley & Ophir D. Klein, 2018. "Parasitic helminths induce fetal-like reversion in the intestinal stem cell niche," Nature, Nature, vol. 559(7712), pages 109-113, July.
  • Handle: RePEc:nat:nature:v:559:y:2018:i:7712:d:10.1038_s41586-018-0257-1
    DOI: 10.1038/s41586-018-0257-1
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    Cited by:

    1. Tsunaki Higa & Yasutaka Okita & Akinobu Matsumoto & Shogo Nakayama & Takeru Oka & Osamu Sugahara & Daisuke Koga & Shoichiro Takeishi & Hirokazu Nakatsumi & Naoki Hosen & Sylvie Robine & Makoto M. Take, 2022. "Spatiotemporal reprogramming of differentiated cells underlies regeneration and neoplasia in the intestinal epithelium," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    2. Omid Omrani & Anna Krepelova & Seyed Mohammad Mahdi Rasa & Dovydas Sirvinskas & Jing Lu & Francesco Annunziata & George Garside & Seerat Bajwa & Susanne Reinhardt & Lisa Adam & Sandra Käppel & Nadia D, 2023. "IFNγ-Stat1 axis drives aging-associated loss of intestinal tissue homeostasis and regeneration," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    3. Joana Silva & Ferhat Alkan & Sofia Ramalho & Goda Snieckute & Stefan Prekovic & Ana Krotenberg Garcia & Santiago Hernández-Pérez & Rob Kammen & Danielle Barnum & Liesbeth Hoekman & Maarten Altelaar & , 2022. "Ribosome impairment regulates intestinal stem cell identity via ZAKɑ activation," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    4. 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.
    5. Laura Solé & Teresa Lobo-Jarne & Daniel Álvarez-Villanueva & Josune Alonso-Marañón & Yolanda Guillén & Marta Guix & Irene Sangrador & Catalina Rozalén & Anna Vert & Antonio Barbachano & Joan Lop & Mar, 2022. "p53 wild-type colorectal cancer cells that express a fetal gene signature are associated with metastasis and poor prognosis," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    6. Mara Martín-Alonso & Sharif Iqbal & Pia M. Vornewald & Håvard T. Lindholm & Mirjam J. Damen & Fernando Martínez & Sigrid Hoel & Alberto Díez-Sánchez & Maarten Altelaar & Pekka Katajisto & Alicia G. Ar, 2021. "Smooth muscle-specific MMP17 (MT4-MMP) regulates the intestinal stem cell niche and regeneration after damage," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    7. Clara Morral & Arshad Ayyaz & Hsuan-Cheng Kuo & Mardi Fink & Ioannis I. Verginadis & Andrea R. Daniel & Danielle N. Burner & Lucy M. Driver & Sloane Satow & Stephanie Hasapis & Reem Ghinnagow & Lixia , 2024. "p53 promotes revival stem cells in the regenerating intestine after severe radiation injury," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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