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

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. Hodder, Lai Mun Wang, Aik Seng Ng, Elizabeth Jennings, Kim S. Midwood, Neesha Dedi, Shazia Irshad, Rachel A. Ridgway, Toby J. Phesse, James East, Ian PM Tomlinson, Gareth CG Davies, Owen J. Sansom and Simon J. Leedham
Additional contact information
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
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
Rachel A. Ridgway: Cancer Research UK Scotland Centre
Toby J. Phesse: University of Oxford
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
Simon J. Leedham: University of Oxford

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-60364-6

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