Joep Beumer, Jens Puschhof, Julia Bauza-Martinez, Adriana Martinez-Silgado, Rasa Elmentaite, Kylie R James, Alexander Ross, Delilah Hendriks, Benedetta Artegiani, Georg A Busslinger, Bas Ponsioen, Amanda Andersson-Rolf, Aurelia Saftien, Charelle Boot, Kai Kretzschmar, Maarten H Geurts, Yotam E Bar-Ephraim, Cayetano Pleguezuelos-Manzano, Yorick Post, Harry Begthel, Franka van der Linden, Carmen Lopez-Iglesias, Willine J van de Wetering, Reinier van der Linden, Peter J Peters, Albert J R Heck, Joachim Goedhart, Hugo Snippert, Matthias Zilbauer, Sarah A Teichmann, Wei Wu, Hans Clevers
Enteroendocrine cells (EECs) sense intestinal content and release hormones to regulate gastrointestinal activity, systemic metabolism, and food intake. Little is known about the molecular make-up of human EEC subtypes and the regulated secretion of individual hormones. Here, we describe an organoid-based platform for functional studies of human EECs. EEC formation is induced in vitro by transient expression of NEUROG3. A set of gut organoids was engineered in which the major hormones are fluorescently tagged. A single-cell mRNA atlas was generated for the different EEC subtypes, and their secreted products were recorded by mass-spectrometry. We note key differences to murine EECs, including hormones, sensory receptors, and transcription factors. Notably, several hormone-like molecules were identified. Inter-EEC communication is exemplified by secretin-induced GLP-1 secretion. Indeed, individual EEC subtypes carry receptors for various EEC hormones. This study provides a rich resource to study human EEC development and function.