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bioRxiv · 10.1101/2024.04.28.591245

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

Mulholland, E. J.·Belnoue-Davis, H. L.·Valbuena, G. N.·Gunduz, N.·Ligeza, A.·Biswas, S.·Gil Vasquez, E.·Omwenga, S.·Nasreddin, N.·Hodder, M.·Wang, L. M.·Irshad, S.·Ng, A. S.·Jennings, E. K.·Midwood, K. S.·Dedi, N.·Ridgeway, R.·Phesse, T.·East, J. E.·Tomlinson, I. P. M.·Davies, G. C. G.·Sansom, O. J.·Leedham, S. J.
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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 Bone Morphogenetic Protein (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. One Sentence SummaryPathological epithelial GREM1 expression induces therapeutically reversible ectopic stem cell niches through stromal remodelling

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Mulholland, E. J., Belnoue-Davis, H. L., Valbuena, G. N., Gunduz, N., Ligeza, A., Biswas, S., Gil Vasquez, E., Omwenga, S., Nasreddin, N., Hodder, M., Wang, L. M., Irshad, S., Ng, A. S., Jennings, E. K., Midwood, K. S., Dedi, N., Ridgeway, R., Phesse, T., East, J. E., Tomlinson, I. P. M., Davies, G. C. G., Sansom, O. J., Leedham, S. J.. 2024-04-30. GREMLIN1 disrupts intestinal epithelial-mesenchymal crosstalk to induce a wnt-dependent ectopic stem cell niche via stromal remodelling. https://doi.org/10.1101/2024.04.28.591245

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