Journal article
Epithelial GREMLIN1 disrupts intestinal epithelial-mesenchymal crosstalk to induce a wnt-dependent ectopic stem cell niche through stromal remodelling
- 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 used 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, resulted in ectopic crypt formation with lineage tracing demonstrating the presence of Lgr5(-) stem/progenitor cells. Isolated epithelial cell Grem1 expression had no effect on individual cell fate indicating an intercompartmental impact of mucosal-wide BMP antagonism. Treatment with a novel anti-Grem1 antibody abrogated the polyposis phenotype, and triangulation of specific pathway inhibitors defined a pathological sequence of events, with wnt-ligand dependent ectopic stem cell niches formed 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.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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- Publisher copy:
- 10.1038/s41467-025-60364-6
Authors
+ Wellcome Trust
More from this funder
- Funder identifier:
- https://ror.org/029chgv08
- Grant:
- 206314/Z/17/Z
- 090532/Z/09/Z
+ Cancer Research UK
More from this funder
- Funder identifier:
- https://ror.org/054225q67
- Grant:
- DRCNPG-Jun22\100002
- A26825
- A28223
+ Italian Association for Cancer Research
More from this funder
- Funder identifier:
- https://ror.org/02g2x7380
- Grant:
- 22795
+ Asociación Española Contra el Cáncer
More from this funder
- Funder identifier:
- https://ror.org/00gxct719
- Grant:
- GEACC18004TAB
- Publisher:
- Springer Nature
- Journal:
- Nature Communications More from this journal
- Volume:
- 16
- Issue:
- 1
- Article number:
- 5167
- Publication date:
- 2025-06-04
- Acceptance date:
- 2025-05-19
- DOI:
- EISSN:
-
2041-1723
- Language:
-
English
- Pubs id:
-
2105585
- Local pid:
-
pubs:2105585
- Deposit date:
-
2025-04-07
- ARK identifier:
Terms of use
- Copyright holder:
- Mulholland et al.
- Copyright date:
- 2025
- Rights statement:
- © The Author(s) 2025. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
- Licence:
- CC Attribution (CC BY)
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