Description and functional validation of human enteroendocrine cell sensors
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.
Authors
- Veerle Geurts (ORCID: https://orcid.org/0009-0000-4758-1883)
- Georg Busslinger (ORCID: https://orcid.org/0000-0002-7851-9895)
- Fjodor A. Yousef Yengej
- Charelle Boot
- Judith Vivié
- Johan H. van Es (ORCID: https://orcid.org/0000-0002-1338-7078)
- Carmen López‐Iglesias
- Joep Beumer (ORCID: https://orcid.org/0000-0002-2055-4444)
- Willine J. van de Wetering (ORCID: https://orcid.org/0000-0003-0311-978X)
- Peter J. Peters (ORCID: https://orcid.org/0000-0002-2964-5684)
- Adriana Martínez-Silgado
- Daniel Krueger (ORCID: https://orcid.org/0000-0003-1139-7755)
- Kèvin Knoops (ORCID: https://orcid.org/0000-0002-7539-1160)
- Jens Puschhof (ORCID: https://orcid.org/0000-0001-9275-4034)
- Hans Clevers (ORCID: https://orcid.org/0000-0002-3077-5582)
- Franziska Voellmy (ORCID: https://orcid.org/0000-0002-0345-1910)
- Maarten H. Geurts (ORCID: https://orcid.org/0009-0006-8832-3745)
- Dylan Mooijman (ORCID: https://orcid.org/0000-0002-7382-9579)
- Ninouk Akkerman (ORCID: https://orcid.org/0000-0003-0547-3993)
- Amanda Andersson-Rolf (ORCID: https://orcid.org/0000-0002-4262-5370)
Institutions
- Roche (Switzerland) (CH)
- Royal Netherlands Academy of Arts and Sciences (NL)
- University Medical Center Utrecht (NL)
- Maastricht University (NL)
Publication Details
- Journal
- Science
- Published
- 2024-10-17
- DOI
- https://doi.org/10.1126/science.adl1460
- Citations
- 28
- Primary Topic
- Pancreatic function and diabetes
- Type
- article
- Field-Weighted Citation Impact
- 16.04
Funders
- Universitair Medisch Centrum Utrecht