23 July 2018

Hormone switching cells in the intestine

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The Clevers group of the Hubrecht Institute shows in a new publication in Nature Cell Biology that endocrine cells of the intestine are able to switch the types of hormones they produce depending on the growth factor BMP.

The small intestine is best known for its capacity to absorb nutrients, which in humans occurs in its 100m2 large epithelial surface, more than half the size of a tennis court. The intestinal epithelium is also home to secretory cell types, cells that produce mucus (Goblet cells) or antimicrobial peptides (Paneth cells). The more unknown side of the intestine is that it is the principle endocrine organ in mammals. This function is fulfilled by the Enteroendocrine cells (EECs), which secrete hormones that influence physiological processes mainly related to food intake such as appetite and insulin release. Because of these functions, EECs are currently heavily investigated as therapeutic targets for diabetes or obesity treatment. This has already led to a widely used diabetes drug that stabilizes a hormone called Glp1, which is a potent inducer of insulin release.


A BMP4-stimulated organoid shows EECs that switched their hormone production towards Secretin (red). Green signals indicate previous Glp1 production, since these cells lack mRNA coding for Glp1. Nuclear stain is shown in blue (DAPI). 

EECs have been described to produce more than 10 different types of hormones. These cells are classified according to their main hormone product and EECs were believed to be separate cell lineages. The Clevers group now shows that EECs can adjust their hormone repertoire over their lifetime, suggesting there are fewer of these different lineages than anticipated before. The authors made use of a combination of techniques such as small intestinal organoids from mice and humans, lineage tracing in vivo and single-cell RNA sequencing. By manipulating different signaling pathways, they found that EECs obtain a different hormone expression pattern upon activation of the BMP signaling pathway. BMP signaling is normally low in the intestinal crypt, where stem cells reside and EECs are born, and high in the villus, where all mature cells eventually die. During this journey from crypt to villus, the current study now showed that EECs can switch their hormone products under influence of this BMP gradient. Blocking BMP signaling in mice could prevent this hormone switch in EECs, and induces hormones in the villus that are normally found only in the crypt such as Glp1. Influencing BMP signaling could thus be a potential avenue to influence EEC hormone expression in humans, and be relevant for diseases such as obesity and diabetes.

Enteroendocrine cells switch hormone expression along the crypt-to-villus BMP signaling gradient Joep Beumer, Benedetta Artegiani, Yorick Post, Frank Reimann, Fiona Gribble, Thuc Nghi Nguyen, Hongkui Zeng, Maaike Van den Born, Johan H. Van Esand Hans Clevers. Nature Cell Biology

Hans Clevers is group leader at the Hubrecht Institute for Developmental Biology and Stem Cell Research and professor of Molecular Genetics at the University Medical Center Utrecht and Utrecht University. He is also Director Research of the Princess Máxima Center for Pediatric Oncology and Oncode Investigator.