53 - Placental Signaling pathways disrupted in Fetal Growth Restriction Model are corrected with IGF-1 Nanoparticle Treatment

Fetal growth restriction (FGR) impacts 5-10% of all live births in the developed world, and there is little intervention available. In Guinea Pigs, using maternal diet restriction to model FGR we have developed IGF-1 placenta-specific nanoparticle therapy to intervene. Here we used RNAseq and transcriptomic analysis to elucidate the differential effects of diet and treatment on placental gene expression.

Study Design: Female Dunkin Hartley Guinea Pigs were fed 70% of normal food intake from 4 weeks prior to mating until gestational day (GD) 30, and then 90%. At GD31.5±1.5 control and restricted animals received ultrasound-guided intra-placental injections of IGF-1-Nanoparticle or PBS-sham. Animals were sacrificed 5 days later, placental tissues collected, and RNA isolated. RNAseq utilized Illumina technology, and differential expression (DE) analysis was performed (DESeq2) with an FDR-corrected P-value threshold of 0.05 and 1.5-fold change. Over-representation of pathways within DE genes was assessed using Reactome.

Results: Differential expression of 332 genes was seen in the placentas of diet restricted animals Vs. control. Restricted animals receiving nanoparticle treatment demonstrated only 23 DE genes compared to control. Over-representation of pathways such as PI3K/AKT signaling (p-value = 0.008) and cell-cell junction organization (p-value = 0.004) was seen in the down-regulated genes of restricted Vs. control. In contrast, pathways over-represented in up-regulated DE genes included cellular response pathways to stress (p=4.34E-08), starvation (p=1.11E-16), and hypoxia (p=0.002).

Conclusion: In our restriction model, differentially expressed genes in the placenta were in critical pathways commonly altered in human FGR. With nanoparticle-mediated, trophoblast-specific IGF-1 gene delivery we have alleviated these perturbations at mid-pregnancy, showing the potential for IGF-1 nanoparticle treatment in human FGR.