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Single-Cell Analysis Identifies Thymic Maturation Delay in Growth-Restricted Neonatal Mice

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cam.issuedOnline2018-11-01
dc.contributor.authorBacon, Wendi
dc.contributor.authorHamilton, Russell
dc.contributor.authorYu, Ziyi
dc.contributor.authorKieckbusch, Jens
dc.contributor.authorHawkes, Delia
dc.contributor.authorKrzak, Ada
dc.contributor.authorAbell, Chris
dc.contributor.authorColucci, Francesco
dc.contributor.authorCharnock-Jones, Stephen
dc.contributor.orcidHamilton, Russell [0000-0002-0598-3793]
dc.contributor.orcidYu, Ziyi [0000-0003-4420-5836]
dc.contributor.orcidAbell, Chris [0000-0001-9174-1987]
dc.contributor.orcidColucci, Francesco [0000-0001-5193-6376]
dc.contributor.orcidCharnock-Jones, Stephen [0000-0002-2936-4890]
dc.date.accessioned2018-11-23T00:32:56Z
dc.date.available2018-11-23T00:32:56Z
dc.date.issued2018-11-01
dc.description.abstractFetal growth restriction (FGR) causes a wide variety of defects in the neonate which can lead to increased risk of heart disease, diabetes, anxiety and other disorders later in life. However, the effect of FGR on the immune system, is poorly understood. We used a well-characterized mouse model of FGR in which placental Igf-2 production is lost due to deletion of the placental specific Igf-2 P0 promotor. The thymi in such animals were reduced in mass with a ~70% reduction in cellularity. We used single cell RNA sequencing (Drop-Seq) to analyze 7264 thymus cells collected at postnatal day 6. We identified considerable heterogeneity among the Cd8/Cd4 double positive cells with one subcluster showing marked upregulation of transcripts encoding a sub-set of proteins that contribute to the surface of the ribosome. The cells from the FGR animals were underrepresented in this cluster. Furthermore, the distribution of cells from the FGR animals was skewed with a higher proportion of immature double negative cells and fewer mature T- cells. Cell cycle regulator transcripts also varied across clusters. The T-cell deficit in FGR mice persisted into adulthood, even when body and organ weights approached normal levels due to catch-up growth. This finding complements the altered immunity found in growth restricted human infants. This reduction in T-cellularity may have implications for adult immunity, adding to the list of adult conditions in which the in utero environment is a contributory factor.
dc.description.sponsorshipWB and RH are supported by the Centre for Trophoblast Research. WB, RH, ZY, CA and DC are supported by BBSRC award BB/R008590/1. JK was supported by the RoseTrees Trust, A1525 and the Centre for Trophoblast Research Next Generation Fellowship. FC is supported by the Wellcome Trust Investigator Award 200841/Z/16/Z.
dc.identifier.doi10.17863/CAM.33182
dc.identifier.eissn1664-3224
dc.identifier.issn1664-3224
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/285838
dc.language.isoeng
dc.publisherFrontiers Media
dc.publisher.urlhttp://dx.doi.org/10.1101/372862
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectDrop-Seq
dc.subjectT-cell
dc.subjectdevelopmental programming
dc.subjectfetal growth restriction
dc.subjectsingle-cell
dc.subjectthymus
dc.subjectAnimals
dc.subjectAnimals, Newborn
dc.subjectDisease Models, Animal
dc.subjectFemale
dc.subjectFetal Growth Retardation
dc.subjectInsulin-Like Growth Factor II
dc.subjectMale
dc.subjectMice
dc.subjectMice, Inbred C57BL
dc.subjectOrgan Size
dc.subjectPlacenta
dc.subjectPregnancy
dc.subjectSingle-Cell Analysis
dc.subjectThymus Gland
dc.titleSingle-Cell Analysis Identifies Thymic Maturation Delay in Growth-Restricted Neonatal Mice
dc.typeArticle
dcterms.dateAccepted2018-10-12
prism.number2523
prism.publicationDate2018
prism.publicationNameFrontiers in Immunology
prism.volume9
pubs.funder-project-idBiotechnology and Biological Sciences Research Council (BB/R008590/1)
pubs.funder-project-idWellcome Trust (200841/Z/16/Z)
rioxxterms.licenseref.startdate2018-11-01
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
rioxxterms.typeJournal Article/Review
rioxxterms.versionVoR
rioxxterms.versionofrecord10.3389/fimmu.2018.02523

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