High Resolution mRNA and Secretome Atlas of Human Enteroendocrine Cells

Enteroendocrine cells (EECs) sense intestinal content and release hormones to regulate gastrointestinal activity and 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 with murine EECs, including in hormones, sensory receptors and transcription factors. Notably, several novel 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.