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

Mulholland, Eoghan J., Belnoue-Davis, Hayley L., Valbuena, Gabriel N., Gunduz, Nuray, Ligeza, Amelia, Lin, Muyang, Biswas, Sujata, Gil Vasquez, Ester, Omwenga, Sulochana, Nasreddin, Nadia, Hodder, Michael C., Wang, Lai Mun, Ng, Aik Seng, Jennings, Elizabeth, Midwood, Kim S., Dedi, Neesha, Irshad, Shazia, Ridgway, Rachel A., Phesse, Toby J. ORCID: https://orcid.org/0000-0001-9568-4916, East, James, Tomlinson, Ian PM, Davies, Gareth CG, Sansom, Owen J. ORCID: https://orcid.org/0000-0001-9540-3010 and Leedham, Simon J. 2025. Epithelial GREMLIN1 disrupts intestinal epithelial-mesenchymal crosstalk to induce a wnt-dependent ectopic stem cell niche through stromal remodelling. Nature Communications 16 (1) , 5167. 10.1038/s41467-025-60364-6

	PDF - Supplemental Material Download (1MB)
	PDF - Supplemental Material Download (123kB)
	PDF - Published Version Download (25MB)

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.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Schools > Biosciences
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/, Type: open-access
Publisher:	Nature Research
ISSN:	2041-1723
Date of First Compliant Deposit:	11 June 2025
Date of Acceptance:	19 May 2025
Last Modified:	11 Jun 2025 09:15
URI:	https://orca.cardiff.ac.uk/id/eprint/178992

Actions (repository staff only)

Edit Item