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
- Simon J. Leedham
2025-06-04
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.