GSE202983
Fetal growth restriction through parental and  fetal immune gene variation and intercellular communications cascade
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. Overall design: We built a mouse single cell atlas of uterine NK cells at mid-gesttaion (gd9.5), using both full length scRNA-seq and 3' droplet-based scRNA-Seq, from the three different mating groups: KIR x C*05 (FGR), WT x C*05 (control 1) and C*05/KIR x WT mice (control 2). In the full length scRNA-seq cohort, we had five replicates per mating group; in the 3' droplet-based scRNA-Seq cohort, we had four replicates for WT x C*05 (control 1) and three replicates each for KIR x C*05 (FGR) and C*05/KIR x WT (control 2). We also analysed all cell types at the maternal-fetal interface at mid-gestation using droplet-based scRNA-seq from the three different mating groups, with three replicates per mating group.