Mid-Pregnancy Placental Transcriptome in a Model of Placental Insufficiency with and without Novel Intervention

Abstract

Fetal growth restriction (FGR) affects between 5-10% of all live births. Placental insufficiency is a leading cause of FGR, resulting in reduced nutrient and oxygen delivery to the fetus. Currently, there are no effective in utero treatment options for FGR, or placental insufficiency. We have developed a gene therapy to deliver, via a non-viral nanoparticle, human insulin-like 1 growth factor (hIGF1) to the placenta as a potential treatment for placenta insufficiency and FGR. Using a guinea pig maternal nutrient restriction (MNR) model of FGR, we aimed to understand the transcriptional changes within the placenta associated with placental insufficiency that occur prior to/at initiation of FGR, and the impact of short-term hIGF1 nanoparticle treatment. Using RNAsequencing, we analyzed protein coding genes of three experimental groups: Control and MNR dams receiving a sham treatment, and MNR dams receiving hIGF1 nanoparticle treatment. Pathway enrichment analysis comparing differentially expressed genelists in sham-treated MNR placentas to sham-treated Control revealed upregulation of pathways associated with degradation and repair of genetic information and downregulation of pathways associated with transmembrane transport. When compared to sham-treated MNR placentas, MNR + hIGF1 placentas demonstrated changes to genelists associated with transmembrane transporter activity including ion, vitamin and solute carrier transport. Overall, this study identifies the key signaling and metabolic changes occurring in the placenta contributing to placental insufficiency prior to/at initiation of FGR, and increases our understanding of the pathways that our nanoparticle-mediated gene therapy intervention regulates.

Keywords: Fetal growth restriction; IGF1; Nanoparticle; Placenta; Placental insufficiency.

Fig. 1

Differential gene expression analysis in the guinea pig placenta at mid-pregnancy. A. Principal component analysis (PCA) on normalized expression data showed no separation of samples by fetal sex. n = 12 female and 12 male. B. Number of upregulated and down regulated differentially expressed genes comparing Control and maternal nutrient restriction (MNR), Control and MNR + hIGF1 nanoparticle treatment, and MNR and MNR + hIGF1. n = 8 Control, 8 MNR and 8 MNR + hIGF1. C. Heat map of differentially expressed genes across Control, MNR and MNR + hIGF1