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Epithelial GREMLIN1 disrupts intestinal epithelial-mesenchymal crosstalk to induce a wnt-dependent ectopic stem cell niche through stromal remodelling

Author

Listed:
  • Eoghan J. Mulholland

    (University of Oxford)

  • Hayley L. Belnoue-Davis

    (University of Oxford)

  • Gabriel N. Valbuena

    (University of Oxford)

  • Nuray Gunduz

    (Cancer Research UK Scotland Centre)

  • Amelia Ligeza

    (University of Oxford)

  • Muyang Lin

    (University of Oxford)

  • Sujata Biswas

    (University of Oxford)

  • Ester Gil Vasquez

    (University of Oxford)

  • Sulochana Omwenga

    (University of Oxford)

  • Nadia Nasreddin

    (University of Oxford)

  • Michael C. Hodder

    (Cancer Research UK Scotland Centre
    University of Glasgow)

  • Lai Mun Wang

    (Changi General Hospital)

  • Aik Seng Ng

    (University of Oxford)

  • Elizabeth Jennings

    (Rheumatology and Musculoskeletal Science University of Oxford)

  • Kim S. Midwood

    (Rheumatology and Musculoskeletal Science University of Oxford)

  • Neesha Dedi

    (UK Research, UCB Pharma)

  • Shazia Irshad

    (University of Oxford
    University of Oxford)

  • Rachel A. Ridgway

    (Cancer Research UK Scotland Centre)

  • Toby J. Phesse

    (University of Oxford
    Cardiff University)

  • James East

    (University of Oxford, and Oxford NIHR Biomedical Research Centre)

  • Ian PM Tomlinson

    (University of Oxford)

  • Gareth CG Davies

    (UK Research, UCB Pharma)

  • Owen J. Sansom

    (Cancer Research UK Scotland Centre
    University of Glasgow)

  • Simon J. Leedham

    (University of Oxford
    University of Oxford, and Oxford NIHR Biomedical Research Centre)

Abstract

In homeostasis, counterbalanced morphogen signalling gradients along the vertical axis of the intestinal mucosa regulate the fate and function of epithelial and stromal cell compartments. Here, we use a disease-positioned mouse and human tissue to explore the consequences of pathological BMP signalling dysregulation on epithelial-mesenchymal interaction. Aberrant pan-epithelial expression of the secreted BMP antagonist Grem1 results in ectopic crypt formation, with lineage tracing demonstrating the presence of Lgr5(−) stem/progenitor cells. Isolated epithelial cell Grem1 expression has no effect on individual cell fate, indicating an intercompartmental impact of mucosal-wide BMP antagonism. Treatment with an anti-Grem1 antibody abrogates the polyposis phenotype, and triangulation of specific pathway inhibitors defines a pathological sequence of events, with Wnt-ligand-dependent ectopic stem cell niches forming through stromal remodelling following BMP disruption. These data support an emerging co-evolutionary model of intestinal cell compartmentalisation based on bidirectional regulation of epithelial-mesenchymal cell fate and function.

Suggested Citation

  • Eoghan J. Mulholland & Hayley L. Belnoue-Davis & Gabriel N. Valbuena & Nuray Gunduz & Amelia Ligeza & Muyang Lin & Sujata Biswas & Ester Gil Vasquez & Sulochana Omwenga & Nadia Nasreddin & Michael C. , 2025. "Epithelial GREMLIN1 disrupts intestinal epithelial-mesenchymal crosstalk to induce a wnt-dependent ectopic stem cell niche through stromal remodelling," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60364-6
    DOI: 10.1038/s41467-025-60364-6
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    References listed on IDEAS

    as
    1. Manqiang Lin & Kimberly Hartl & Julian Heuberger & Giulia Beccaceci & Hilmar Berger & Hao Li & Lichao Liu & Stefanie Müllerke & Thomas Conrad & Felix Heymann & Andrew Woehler & Frank Tacke & Nikolaus , 2023. "Establishment of gastrointestinal assembloids to study the interplay between epithelial crypts and their mesenchymal niche," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    2. Linxiang Lan & Theodore Evan & Huafu Li & Aasia Hussain & E. Josue Ruiz & May Zaw Thin & Rute M. M. Ferreira & Hari Ps & Eva M. Riising & Yoh Zen & Jorge Almagro & Kevin W. Ng & Pablo Soro-Barrio & Je, 2022. "GREM1 is required to maintain cellular heterogeneity in pancreatic cancer," Nature, Nature, vol. 607(7917), pages 163-168, July.
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