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dc.contributor.authorGlass, LL
dc.contributor.authorCalero Nieto, F
dc.contributor.authorJawaid, W
dc.contributor.authorLarraufie, P
dc.contributor.authorKay, RG
dc.contributor.authorGottgens, B
dc.contributor.authorReimann, F
dc.contributor.authorGribble, FM
dc.date.accessioned2017-09-29T17:02:04Z
dc.date.available2017-09-29T17:02:04Z
dc.date.issued2017-10
dc.identifier.issn2212-8778
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/267461
dc.description.abstractObjectives: To identify sub-populations of intestinal preproglucagon-expressing (PPG) cells producing Glucagon-like Peptide-1, and their associated expression profiles of sensory receptors, thereby enabling the discovery of therapeutic strategies that target these cell populations for the treatment of diabetes and obesity. Methods: We performed single cell RNA sequencing of PPG-cells purified by flow cytometry from the upper small intestine of 3 GLU-Venus mice. Cells from 2 mice were sequenced at low depth, and from the third mouse at high depth. High quality sequencing data from 234 PPG-cells were used to identify clusters by tSNE analysis. qPCR was performed to compare the longitudinal and crypt/villus locations of cluster-specific genes. Immunofluorescence and mass spectrometry were used to confirm protein expression. Results: PPG-cells formed 3 major clusters: a group with typical characteristics of classical L-cells, including high expression of Gcg and Pyy (comprising 51% of all PPG-cells); a cell type overlapping with Gip-expressing K-cells (14%); and a unique cluster expressing Tph1 and Pzp that was predominantly located in proximal small intestine villi and co-produced 5-HT (35%). Expression of G-protein coupled receptors differed between clusters, suggesting the cell types are differentially regulated, and would be differentially targetable. Conclusions: Our findings support the emerging concept that many enteroendocrine cell populations are highly overlapping, with individual cells producing a range of peptides previously assigned to distinct cell types. Different receptor expression profiles across the clusters highlight potential drug targets to increase gut hormone secretion for the treatment of diabetes and obesity.
dc.description.sponsorshipResearch in the FR/FMG lab is funded by a Wellcome joint investigator award (106262/Z/14/Z and 106263/Z/14/Z) and a joint MRC programme within the Metabolic Diseases Unit (MRC_MC_UU_12012/3). Single cell collection and analysis was supported through MRC Clinical Research Infrastructure funds for the Cambridge Single Cell Analysis Clinical Core Facility. Work in the Göttgens laboratory is supported by grants from the Wellcome Trust, Bloodwise, Cancer Research UK, NIDDK and core support grants by the Wellcome Trust to the Wellcome Trust-MRC Cambridge Stem Cell Institute.
dc.publisherElsevier
dc.rightsAttribution 4.0 International
dc.subjectSingle cell RNA seq
dc.subjectGLP-1
dc.subjectPPG-cells
dc.subjectL-cells
dc.subjectMass spectrometry
dc.subject5-HT
dc.titleSingle-cell RNA-sequencing reveals a distinct population of proglucagon-expressing cells specific to the mouse upper small intestine
dc.typeArticle
prism.publicationNameMolecular Metabolism
dc.identifier.doi10.17863/CAM.12414
dcterms.dateAccepted2017-07-27
rioxxterms.versionofrecord10.1016/j.molmet.2017.07.014
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
rioxxterms.licenseref.startdate2017-07-27
dc.contributor.orcidGlass, Leslie [0000-0002-3559-4705]
dc.contributor.orcidCalero Nieto, Fernando [0000-0003-3358-8253]
dc.contributor.orcidJawaid, Wajid [0000-0002-4861-6694]
dc.contributor.orcidLarraufie, Pierre [0000-0001-7718-6200]
dc.contributor.orcidKay, Richard [0000-0002-3827-8687]
dc.contributor.orcidGottgens, Berthold [0000-0001-6302-5705]
dc.contributor.orcidReimann, Frank [0000-0001-9399-6377]
dc.contributor.orcidGribble, Fiona [0000-0002-4232-2898]
dc.identifier.eissn2212-8778
rioxxterms.typeJournal Article/Review
pubs.funder-project-idMedical Research Council (MC_UU_12012/3)
pubs.funder-project-idMedical Research Council (MC_UU_12012/5)
pubs.funder-project-idWellcome Trust (106262/Z/14/Z)
pubs.funder-project-idCancer Research UK (21762)
pubs.funder-project-idLeukaemia & Lymphoma Research (12029)
pubs.funder-project-idNational Institute of Diabetes and Digestive and Kidney Diseases (R24DK106766)
pubs.funder-project-idMedical Research Council (MC_PC_12009)
pubs.funder-project-idMedical Research Council (MR/M008975/1)
pubs.funder-project-idMedical Research Council (MR/M009041/1)
pubs.funder-project-idWellcome Trust (088357/Z/09/Z)
pubs.funder-project-idWellcome Trust (084210/Z/07/Z)
pubs.funder-project-idMedical Research Council (MC_UU_12012/1)
pubs.funder-project-idWellcome Trust (097922/Z/11/Z)
pubs.funder-project-idWellcome Trust (105031/D/14/Z)
pubs.funder-project-idMedical Research Council (MR/M024873/1)
cam.issuedOnline2017-08-01
datacite.issupplementedby.doi10.1016/j.molmet.2017.07.014


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