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.
Show 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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