Single cell transcriptomic profiling of large intestinal enteroendocrine cells in mice – Identification of selective stimuli for insulin-like peptide-5 and glucagon-like peptide-1 co-expressing cells
| Autor: | Fiona M. Gribble, Jo E. Lewis, Richard G. Kay, Pierre Larraufie, Joyce Li, Frank Reimann, Brian Y.H. Lam, Giles Sh Yeo, Deborah A. Goldspink, Andrew B. Leiter, Lawrence J. Billing |
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| Přispěvatelé: | Wellcome Trust-MRC Institute of Metabolic Science, Reimann, Frank [0000-0001-9399-6377], Larraufie, Pierre [0000-0001-7718-6200], Yeo, Giles [0000-0001-8823-3615], Kay, Richard [0000-0002-3827-8687], Gribble, Fiona [0000-0002-4232-2898], Apollo - University of Cambridge Repository |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine lcsh:Internal medicine Mice Transgenic 030209 endocrinology & metabolism Enteroendocrine cell [SDV.BC]Life Sciences [q-bio]/Cellular Biology Tryptophan Hydroxylase Receptor Angiotensin Type 1 Secretin Mice 03 medical and health sciences 0302 clinical medicine Single-cell analysis Glucagon-Like Peptide 1 Animals Insulin Peptide YY Intestine Large Receptor lcsh:RC31-1245 Insulin-like peptide-5 (Insl5) Molecular Biology Cholecystokinin Enteroendocrine cells Chemistry Serotonin (5-HT) Single cell RNA-sequencing digestive oral and skin physiology Proteins Cell Biology [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism Angiotensin II 3. Good health Cell biology Mice Inbred C57BL 030104 developmental biology Enterochromaffin cell Female Original Article Single-Cell Analysis Transcriptome Corrigendum hormones hormone substitutes and hormone antagonists Glucagon-like peptide-1 (GLP-1) |
| Zdroj: | Molecular metabolism Molecular metabolism, Elsevier, 2019, 29, pp.158-169. ⟨10.1016/j.molmet.2019.09.001⟩ Molecular Metabolism, Vol 29, Iss, Pp 158-169 (2019) Molecular Metabolism Mol Metab |
| ISSN: | 2212-8778 |
| DOI: | 10.1016/j.molmet.2019.09.001⟩ |
| Popis: | Objective Enteroendocrine cells (EECs) of the large intestine, found scattered in the epithelial layer, are known to express different hormones, with at least partial co-expression of different hormones in the same cell. Here we aimed to categorize colonic EECs and to identify possible targets for selective recruitment of hormones. Methods Single cell RNA-sequencing of sorted enteroendocrine cells, using NeuroD1-Cre x Rosa26-EYFP mice, was used to cluster EECs from the colon and rectum according to their transcriptome. G-protein coupled receptors differentially expressed across clusters were identified, and, as a proof of principle, agonists of Agtr1a and Avpr1b were tested as candidate EEC secretagogues in vitro and in vivo. Results EECs from the large intestine separated into 7 clear clusters, 4 expressing higher levels of Tph1 (enzyme required for serotonin (5-HT) synthesis; enterochromaffin cells), 2 enriched for Gcg (encoding glucagon-like peptide-1, GLP-1, L-cells), and the 7th expressing somatostatin (D-cells). Restricted analysis of L-cells identified 4 L-cell sub-clusters, exhibiting differential expression of Gcg, Pyy (Peptide YY), Nts (neurotensin), Insl5 (insulin-like peptide 5), Cck (cholecystokinin), and Sct (secretin). Expression profiles of L- and enterochromaffin cells revealed the clustering to represent gradients along the crypt-surface (cell maturation) and proximal-distal gut axes. Distal colonic/rectal L-cells differentially expressed Agtr1a and the ligand angiotensin II was shown to selectively increase GLP-1 and PYY release in vitro and GLP-1 in vivo. Conclusion EECs in the large intestine exhibit differential expression gradients along the crypt-surface and proximal-distal axes. Distal L-cells can be differentially stimulated by targeting receptors such as Agtr1a. Graphical abstract Image 1 Highlights • Large intestinal enteroendocrine cells group into subclusters by single cell RNAseq. • Enteroendocrine-cell subclusters differ along crypt-surface and longitudinal axes. • L-cells differ longitudinally by production of NTS (proximal colon) or INSL5 (rectum). • INSL5-positive cells express distinct GPCRs enabling cluster-specific stimulation. • Targeted stimulation of INSL5-producing L-cells elevates plasma GLP-1 and PYY in vivo. |
| Databáze: | OpenAIRE |
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