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Fetal growth restriction through parental and fetal immune gene variation and intercellular communications cascade

ABSTRACT: Fetal growth restriction (FGR) affects 5-10% of pregnancies worldwide, and can have serious consequences for both mother and child. Both preventative and treatment strategies are currently largely lacking due to a poor understanding of the pathogenesis of FGR. There is strong genetic evidence for the involvement of KIR and HLA genes in FGR, however, the specific HLA and KIR risk alleles and their functional effects have been difficult to map due to linkage disequilibrium, maternal and paternal influence, and an inability to investigate pathological human pregnancies at critical early gestational stages. Here we demonstrate that the interaction between two defined genes, the maternal KIR2DL1 expressed on uterine natural killer (NK) cells, and the paternally-inherited HLA-C*0501, expressed on fetal trophoblast cells, leads to FGR in a humanised mouse model. We show that the initial KIR2DL1 and C*0501 interaction leads to pathogenic uterine arterial remodeling and a modulation of uterine NK cell function. We delineate how this initial effect cascades to changes in transcriptional expression and intercellular communication in a myriad of cell types and pathways at the maternal-fetal interface. These findings reveal new mechanistic insight into the importance of specific KIR and HLA risk alleles in FGR, and provide new avenues of prevention and treatment to reduce disease burden and improve long-term health outcomes of the child.

ORGANISM(S): Mus musculus

PROVIDER: GSE202983 | GEO | 2022/05/20

REPOSITORIES: GEO

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Project description:Worldwide, fetal growth restriction (FGR) affects 7 to 10% of pregnancies, or roughly 20.5 million infants, each year. FGR not only increases neonatal mortality and morbidity but also the risk of obesity in later life. Currently, the molecular mechanisms by which FGR "programs" an obese phenotype are not well understood. Studies demonstrate that FGR females are more prone to obesity compared to males; however, the molecular mechanisms that lead to the sexually dimorphic programming of FGR are not known. Thus, we hypothesized that FGR leads to the sexually dimorphic programming of preadipocytes and reduces their ability to differentiate into mature adipocytes. To test the hypothesis, we utilized a maternal hyperthermia-induced placental insufficiency to restrict fetal growth in sheep. We collected perirenal adipose tissue from male and female near-term FGR and normal-weight fetal lambs (N=4 in each group, 16 total), examined the preadipocytes' differentiation potential, and identified differential mRNA transcript expression in perirenal adipose tissue. Male FGR fetuses have lower cellular density compared to control male fetuses. However, no difference was observed in female FGR fetuses compared to control female fetuses. In addition, the ability of preadipocytes to differentiate into mature adipocytes with fat accumulation was impaired in male FGR fetuses, but this was not observed in female FGR fetuses. Finally, we examined the genes and pathways involved in the sexually dimorphic programming of obesity by FGR. On enrichment of differentially expressed genes in males compared to females, the Thermogenesis KEGG Pathway was downregulated, and the Metabolic and Steroid Biosynthesis KEGG pathways were upregulated. On enrichment of differentially expressed genes in male FGR compared to male control, the Steroid Biosynthesis KEGG Pathway was downregulated, and the PPAR Signaling KEGG pathway was upregulated. No pathways were altered in females in response to growth restriction in perirenal adipose tissue. Thus, the present study demonstrates a sexually dimorphic program in response to growth restriction in sheep fetal perirenal adipose tissue.

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Fetal growth restriction through parental and fetal immune gene variation and intercellular communications cascade

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