Link to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2022.11.11.516138v1?rss=1

Authors: Valenta, T., Berkova, L., Fazilaty, H., Yang, Q., Kubovciak, J., Stastna, M., Hrckulak, D., Vojtechova, M., Brugger, M., Hausmann, G., Liberali, P., Korinek, V., Basler, K.

Abstract:
The protective and absorptive functions of the intestinal epithelium rely on differentiated enterocytes. Their differentiation is orchestrated by sub-epithelial mesenchymal cells producing ligands along the villus axis, in particular Bmps and Tgf{beta}. Here we show that individual Bmp ligands and Tgf{beta} drive distinct enterocytic programs specific to villus zonation. Bmp4 is expressed mainly from the center to the upper part of the villus, and it activates preferentially genes connected to lipid uptake and metabolism. In contrast, Bmp2 is produced by villus-tip mesenchymal cells, and it influences the adhesive properties of villus-tip epithelial cells and the expression of immunomodulators. Hence, Bmp2 promotes the terminal enterocytic differentiation at the villus-tip. Additionally, Tgf{beta} induces epithelial gene expression programs similar to that triggered by Bmp2. Bmp2-driven villus-tip program is activated by a canonical BmpRI/Smad-dependent mechanism. Finally, we established an organoid cultivation system that enriches for villus-tip enterocytes and thereby better mimics the cellular composition of the intestinal epithelium. Altogether our data suggest that not only Bmp gradient, but also the activity of individual Bmp drives specific enterocytic programs.

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