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dc.contributor.authorPrior, Nicoleen
dc.contributor.authorHindley, Christopheren
dc.contributor.authorRost, Fabianen
dc.contributor.authorMeléndez, Elenaen
dc.contributor.authorLau, Winnieen
dc.contributor.authorGottgens, Bertholden
dc.contributor.authorRulands, Steffenen
dc.contributor.authorSimons, Benjaminen
dc.contributor.authorHuch Ortega, Meritxellen
dc.date.accessioned2019-05-17T23:30:13Z
dc.date.available2019-05-17T23:30:13Z
dc.date.issued2019-06-12en
dc.identifier.issn0950-1991
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/292965
dc.description.abstractDuring mouse embryogenesis, progenitors within the liver known as hepatoblasts give rise to adult hepatocytes and cholangiocytes. Hepatoblasts, which are specified at E8.5-E9.0, have been regarded as a homogeneous progenitor population that initiate differentiation from E13.5. Recently, scRNA-seq analysis has identified sub-populations of transcriptionally distinct hepatoblasts at E11.5. Here we show that hepatoblasts are not only transcriptionally but also functionally heterogeneous, and that a sub-population of E9.5-E10.0 hepatoblasts exhibit a previously unidentified early-commitment to cholangiocyte fate. Importantly, we also identify a sub-population constituting 2% of E9.5-E10.0 hepatoblasts that express the adult stem cell marker Lgr5, and generate both hepatocyte and cholangiocyte progeny that persist for the life span of the mouse. Combining lineage tracing and scRNA-seq, we show that Lgr5 marks E9.5-E10.0 bipotent liver progenitors residing at the apex of a hepatoblast hierarchy. Notably, isolated Lgr5+ hepatoblasts can be clonally expanded in vitro into embryonic liver organoids, which can commit to either hepatocyte or cholangiocyte fates. Our study demonstrates functional heterogeneity within E9.5 hepatoblasts and identifies Lgr5 as a marker for a sub53 population of bipotent liver progenitors.
dc.description.sponsorshipM.H. is a Wellcome Trust Sir Henry Dale Fellow and is jointly funded by the Wellcome Trust and the Royal Society (104151/Z/14/Z); M.H. and N.P. are funded by a Horizon 2020 grant (LSFM4LIFE). C.H. was funded by a Cambridge Stem Cell Institute Seed funding for interdisciplinary research awarded to M.H. and B.D.S., B.D.S acknowledges funding from the Royal Society E.P. Abraham Research Professorship (RP\R1\180165) and Wellcome Trust (098357/Z/12/Z). W.L. and B.G. were supported by programmatic funding from the Wellcome Trust, CRUK and Bloodwise, core infrastructure support from the Wellcome and MRC to the Wellcome & MRC Cambridge Stem Cell Institute, and an MRC Clinical Research Infrastructure grant supporting single cell molecular analysis. S.R. was funded on a Herchel-Smith Fellowship. The authors acknowledge core funding to the Gurdon Institute from the Wellcome Trust (092096) and CRUK (C6946/A14492).
dc.format.mediumElectronicen
dc.languageengen
dc.publisherCompany of Biologists
dc.rightsAll rights reserved
dc.rights.uri
dc.subjectLiveren
dc.subjectCells, Cultureden
dc.subjectEpithelial Cellsen
dc.subjectHepatocytesen
dc.subjectStem Cellsen
dc.subjectAnimalsen
dc.subjectMiceen
dc.subjectReceptors, G-Protein-Coupleden
dc.subjectMicroscopy, Confocalen
dc.subjectCell Culture Techniquesen
dc.subjectCell Counten
dc.subjectCell Differentiationen
dc.subjectGene Expression Regulation, Developmentalen
dc.subjectBase Sequenceen
dc.subjectCell Lineageen
dc.subjectEmbryonic Developmenten
dc.subjectHomeostasisen
dc.subjectAllelesen
dc.subjectFemaleen
dc.subjectMaleen
dc.titleLgr5<sup>+</sup> stem and progenitor cells reside at the apex of a heterogeneous embryonic hepatoblast pool.en
dc.typeArticle
prism.issueIdentifier12en
prism.publicationDate2019en
prism.publicationNameDevelopment (Cambridge, England)en
prism.volume146en
dc.identifier.doi10.17863/CAM.40115
dcterms.dateAccepted2019-05-15en
rioxxterms.versionofrecord10.1242/dev.174557en
rioxxterms.versionAM
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2019-06-12en
dc.contributor.orcidPrior, Nicole [0000-0003-2856-7052]
dc.contributor.orcidHindley, Christopher [0000-0002-5294-1270]
dc.contributor.orcidRost, Fabian [0000-0001-6466-2589]
dc.contributor.orcidLau, Winnie [0000-0003-1209-1854]
dc.contributor.orcidGottgens, Berthold [0000-0001-6302-5705]
dc.contributor.orcidSimons, Benjamin [0000-0002-3875-7071]
dc.contributor.orcidHuch, Meritxell [0000-0002-1545-5265]
dc.identifier.eissn1477-9129
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idWELLCOME TRUST (098357/Z/12/Z)
pubs.funder-project-idRoyal Society (RP/R1/180165)
pubs.funder-project-idWELLCOME TRUST (105031/D/14/Z)
pubs.funder-project-idWellcome Trust (092096/Z/10/Z)
pubs.funder-project-idCancer Research UK (A14492)
pubs.funder-project-idMRC (MC_PC_12009)
pubs.funder-project-idWELLCOME TRUST (104151/Z/14/Z)
cam.orpheus.successThu Jan 30 10:45:02 GMT 2020 - Embargo updated*
rioxxterms.freetoread.startdate2020-06-12


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