Single-Cell Analysis Identifies Thymic Maturation Delay in Growth-Restricted Neonatal Mice
Fetal 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 FG...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-11-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2018.02523/full |
| _version_ | 1819090838166175744 |
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| author | Wendi A. Bacon Wendi A. Bacon Wendi A. Bacon Russell S. Hamilton Russell S. Hamilton Ziyi Yu Jens Kieckbusch Jens Kieckbusch Delia Hawkes Ada M. Krzak Chris Abell Francesco Colucci Francesco Colucci D. Stephen Charnock-Jones D. Stephen Charnock-Jones |
| author_facet | Wendi A. Bacon Wendi A. Bacon Wendi A. Bacon Russell S. Hamilton Russell S. Hamilton Ziyi Yu Jens Kieckbusch Jens Kieckbusch Delia Hawkes Ada M. Krzak Chris Abell Francesco Colucci Francesco Colucci D. Stephen Charnock-Jones D. Stephen Charnock-Jones |
| author_sort | Wendi A. Bacon |
| collection | DOAJ |
| description | Fetal 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 7,264 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. |
| first_indexed | 2024-12-21T22:30:11Z |
| format | Article |
| id | doaj.art-3dca66eaaa31400e84a13ca5da424fe4 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-21T22:30:11Z |
| publishDate | 2018-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-3dca66eaaa31400e84a13ca5da424fe42022-12-21T18:48:07ZengFrontiers Media S.A.Frontiers in Immunology1664-32242018-11-01910.3389/fimmu.2018.02523416232Single-Cell Analysis Identifies Thymic Maturation Delay in Growth-Restricted Neonatal MiceWendi A. Bacon0Wendi A. Bacon1Wendi A. Bacon2Russell S. Hamilton3Russell S. Hamilton4Ziyi Yu5Jens Kieckbusch6Jens Kieckbusch7Delia Hawkes8Ada M. Krzak9Chris Abell10Francesco Colucci11Francesco Colucci12D. Stephen Charnock-Jones13D. Stephen Charnock-Jones14Department of Obstetrics and Gynaecology, University of Cambridge, Cambridge, United KingdomCentre for Trophoblast Research, University of Cambridge, Cambridge, United KingdomDepartment of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United KingdomCentre for Trophoblast Research, University of Cambridge, Cambridge, United KingdomDepartment of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United KingdomDepartment of Chemistry, University of Cambridge, Cambridge, United KingdomDepartment of Obstetrics and Gynaecology, University of Cambridge, Cambridge, United KingdomCentre for Trophoblast Research, University of Cambridge, Cambridge, United KingdomDepartment of Obstetrics and Gynaecology, University of Cambridge, Cambridge, United KingdomDepartment of Obstetrics and Gynaecology, University of Cambridge, Cambridge, United KingdomDepartment of Chemistry, University of Cambridge, Cambridge, United KingdomDepartment of Obstetrics and Gynaecology, University of Cambridge, Cambridge, United KingdomCentre for Trophoblast Research, University of Cambridge, Cambridge, United KingdomDepartment of Obstetrics and Gynaecology, University of Cambridge, Cambridge, United KingdomCentre for Trophoblast Research, University of Cambridge, Cambridge, United KingdomFetal 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 7,264 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.https://www.frontiersin.org/article/10.3389/fimmu.2018.02523/fullDrop-Seqfetal growth restrictionT-cellthymussingle-celldevelopmental programming |
| spellingShingle | Wendi A. Bacon Wendi A. Bacon Wendi A. Bacon Russell S. Hamilton Russell S. Hamilton Ziyi Yu Jens Kieckbusch Jens Kieckbusch Delia Hawkes Ada M. Krzak Chris Abell Francesco Colucci Francesco Colucci D. Stephen Charnock-Jones D. Stephen Charnock-Jones Single-Cell Analysis Identifies Thymic Maturation Delay in Growth-Restricted Neonatal Mice Frontiers in Immunology Drop-Seq fetal growth restriction T-cell thymus single-cell developmental programming |
| title | Single-Cell Analysis Identifies Thymic Maturation Delay in Growth-Restricted Neonatal Mice |
| title_full | Single-Cell Analysis Identifies Thymic Maturation Delay in Growth-Restricted Neonatal Mice |
| title_fullStr | Single-Cell Analysis Identifies Thymic Maturation Delay in Growth-Restricted Neonatal Mice |
| title_full_unstemmed | Single-Cell Analysis Identifies Thymic Maturation Delay in Growth-Restricted Neonatal Mice |
| title_short | Single-Cell Analysis Identifies Thymic Maturation Delay in Growth-Restricted Neonatal Mice |
| title_sort | single cell analysis identifies thymic maturation delay in growth restricted neonatal mice |
| topic | Drop-Seq fetal growth restriction T-cell thymus single-cell developmental programming |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2018.02523/full |
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