Fetal growth restriction (FGR) is a significant concern in obstetrics, affecting 5–10% of pregnancies globally. FGR is a major contributor to perinatal morbidity and mortality and poses a significant maternal risk due to potential co-occurrence with pre-eclampsia. Despite their impact, the underlying causes, mechanisms, and interrelationship of FGR and pre-eclampsia remain poorly understood.

In this work, Gurman Kaur and coauthors explored the genetic and immunological underpinnings of FGR by developing a humanized transgenic mouse model for studying FGR.  The model enabled study of fetuses carrying two FGR risk alleles, one encoding a killer cell immunoglobulin-like receptor (KIR) found on the surface of uterine natural killer (uNK) cells, and the other a human leukocyte antigen-C (HLA-C) allele encoding a trophoblast KIR ligand. The authors chose alleles, KIR2DL1*0030201 and HLA-C*05:01:01:01, based on frequency in the human population, association with increased risk for FGR, and known binding interactions.

After validating transgene expression and localization in their model, Kaur et al measured fetal weight and observed FGR in fetuses resulting from the pairing of females expressing KIR2DL1 on uNK cells and males expressing HLA-C*05. The authors next investigated the diversity and function of uNK cells at the maternal-fetal interface using scRNA-seq, identifying seven subsets. Topic modeling was subsequently used to detect more nuanced changes in gene programs among subsets, showing the lymphocyte activation program induced and the extracellular matrix and tissue remodeling program repressed in FGR.

To confirm the increased expression of top genes identified by topic modeling, the authors worked with Indica Labs’ Pharma Services for image analysis of colorimetric situ hybridization assays on mid-gestation uterine tissue. The Pharma Services team utilized the HALO® ISH module for quantitative analysis of Anxa2 and Ccl1 RNA probe copies per cell and the HALO Multiplex IHC module for quantification of cells positive for diffuse Gzme/d/g probe staining. The authors and Pharma Services collaborated using the HALO Link image management platform to import sample metadata and for researcher annotation of regions of interest.

Kaur and coauthors’ characterization of transcriptional changes in immune and other cell types at the maternal-fetal interface showed that the interaction of KIR2DL1 and HLA-C*05 results in changes in gene expression and placental pathways in multiple cell types in FGR. These and other results offer insight into the mechanisms of specific FGR risk alleles and suggest potential strategies for prevention and treatment.