High-Resolution mRNA and Secretome Atlas of Human Enteroendocrine Cells

Joep Beumer, Jens Puschhof, Julia Bauzá-Martinez, Adriana Martínez-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 BegthelFranka 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

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)1291-1306.e19
JournalCell
Volume181
Issue number6
DOIs
Publication statusPublished - 11 Jun 2020

Keywords

  • Cells, Cultured
  • Enteroendocrine Cells/metabolism
  • Gastrointestinal Hormones/genetics
  • Gastrointestinal Tract/metabolism
  • Glucagon-Like Peptide 1/genetics
  • Humans
  • Organoids/metabolism
  • RNA, Messenger/genetics
  • Transcription Factors/genetics
  • Transcriptome/genetics
  • secretomics
  • intestine
  • proteomics
  • organoids
  • fluorescent tagging
  • enteroendocrine cell
  • hormone
  • CRISPR-mediated knockin
  • single-cell atlas
  • human

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