Description and functional validation of human enteroendocrine cell sensors
Joep Beumer, Maarten H. Geurts, Veerle Geurts, Amanda Andersson-Rolf, Ninouk Akkerman, Franziska Voellmy, Daniel Krueger, Georg Busslinger, Adriana Martínez-Silgado, Charelle Boot, Fjodor A. Yousef Yengej, Jens Puschhof, Willine J. van de Wetering, Kèvin Knoops, Carmen López‐Iglesias, Peter J. Peters, Judith Vivié, Dylan Mooijman, Johan H. van Es, Hans Clevers
Abstract
Enteroendocrine cells (EECs) are gut epithelial cells that respond to intestinal contents by secreting hormones, including the incretins glucagon-like peptide 1 (GLP-1) and gastric inhibitory protein (GIP), which regulate multiple physiological processes. Hormone release is controlled through metabolite-sensing proteins. Low expression, interspecies differences, and the existence of multiple EEC subtypes have posed challenges to the study of these sensors. We describe differentiation of stomach EECs to complement existing intestinal organoid protocols. CD200 emerged as a pan-EEC surface marker, allowing deep transcriptomic profiling from primary human tissue along the stomach-intestinal tract. We generated loss-of-function mutations in 22 receptors and subjected organoids to ligand-induced secretion experiments. We delineate the role of individual human EEC sensors in the secretion of hormones, including GLP-1. These represent potential pharmacological targets to influence appetite, bowel movement, insulin sensitivity, and mucosal immunity.