Abstract
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.
Highlights
Fetal growth restriction (FGR) is a serious condition affecting between 3 and 7% of infants in developed nations [1] but can be higher than 40% in low-income nations [2]
Given the overall severity in thymocyte reduction, we used Drop-Seq to investigate the effects of FGR at the single-T-cell level
Within the Igf-2 locus, neither WT nor P0 thymocytes cells contained reads aligned to the P0-specific upstream exon U2 (Figure S4), confirming that placental-specific P0 was not expressed in T cells
Summary
Fetal growth restriction (FGR) is a serious condition affecting between 3 and 7% of infants in developed nations [1] but can be higher than 40% in low-income nations [2]. FGR is commonly attributed to insufficient fetal nutrients. This may be because either the mother is malnourished, as in the prototypical case of the Dutch Hunger Winter [4], or because the placenta is dysfunctional, leading to poor nutrient transport to the fetus [5]. Growth restricted infants exhibit asymmetric growth wherein resources are reallocated to the fetal brain at the cost of the rest of the body [6], so called “brain sparing.”. Growth restricted infants exhibit asymmetric growth wherein resources are reallocated to the fetal brain at the cost of the rest of the body [6], so called “brain sparing.” The infants undergo “catch-up growth” for years,
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