New @ScienceMagazine study in collab with @IHB_Research!
We identified novel receptors on enteroendocrine cells (EECs) that regulate secretion of endogenous hormones. These harbor therapeutic potential for metabolic disease. Read the paper go.roche.com/m9hah or 🧵⬇️
Oct 18, 2024 · 9:21 AM UTC
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EECs secrete 20+ hormones (including GLP-1) in response to ingested nutrients. There are 6 EEC subtypes existing in different ratios along the gastrointestinal tract. Their hormones regulate broad aspects of physiology, including appetite and gut motility.
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#Organoids provide a unique model to study the behavior of human EECs from these different regions. In this study, we set out to map the ‘sensory’ proteins that regulate the secretion of these different hormones.
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We prioritized a set of receptor proteins for functional studies. As EECs are exceedingly rare (<1% of the epithelium) and depleted in RNA sequencing studies, we explored surface markers that allowed their purification.
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Checkpoint inhibitor CD200 emerged as a highly specific marker allowing deep transcriptomic profiling of these cells from native human tissue. We generated an atlas of over 1000 EECs using VASA-sequencing, providing full-length transcript coverage.
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We validated many known and found additional novel receptors enriched in these lineages. After prioritizing receptor proteins, we stimulated organoids with their endogenous or synthetic ligands followed by multiplexed measurements of secreted hormones.
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Multiple-specific receptor agonists could drive the secretion of one or multiple intestinal hormones. The majority of the secretion responses were lost after receptor knockout, further evidencing receptor engagement.
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The receptors derived in this study may be explored for therapeutic potential through the modulation of the endogenous hormones. Furthermore, these models can be used for high throughput screening to identify molecules that regulate hormone secretions.
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Great collaboration @_Hubrecht #TeamIHB #pRED @Roche @UMCUtrecht @MaastrichtU and huge thanks to all authors, including @BeumerJoep @geurts_maarten @VeerleGeurts @NinoukAkkerman @DanielKruegerDK @JensPuschhof. We sincerely thank @ERC for the generous funding.
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About the video at top. Mapping the function of nutrient sensors on enteroendocrine cells (EECs): Multiple EECs (purple) producing the hunger hormone Ghrelin in a stomach organoid. Credit: @NinoukAkkerman, @Roche @IHB_Research
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About the human intestinal organoid image: you see typical ‘budding crypts’ and a central ‘villus-like’ domain. Key intestinal cell types are in green, blue, red and purple. Membranes are yellow, nuclei cyan. Credit: Ninouk Akkerman, Yannik Bollen and Jannika Finger; Roche’s IHB
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And of course, the primary work was performed at the @_Hubrecht institute in Utrecht, NL
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