Maternal-fetal interfaces transcriptome changes associated with placental insufficiency and a novel gene therapy intervention

The etiology of fetal growth restriction (FGR) is multifactorial, although many cases often involve placental insufficiency. Placental insufficiency is associated with inadequate trophoblast invasion, resulting in high resistance to blood flow, decreased availability of nutrients, and increased hypoxia. We have developed a nonviral, polymer-based nanoparticle that facilitates delivery and transient gene expression of human insulin-like 1 growth factor (<i>hIGF1</i>) in placental trophoblast for the treatment of placenta insufficiency and FGR. Using the established guinea pig maternal nutrient restriction (MNR) model of placental insufficiency and FGR, the aim of the study was to identify novel pathways in the subplacenta/decidua that provide insight into the underlying mechanism driving placental insufficiency and may be corrected with <i>hIGF1</i> nanoparticle treatment. Pregnant guinea pigs underwent ultrasound-guided sham or <i>hIGF1</i> nanoparticle treatment at midpregnancy, and subplacenta/decidua tissue was collected 5 days later. Transcriptome analysis was performed using RNA Sequencing on the Illumina platform. The MNR subplacenta/decidua demonstrated fewer maternal spiral arteries lined by trophoblast, shallower trophoblast invasion, and downregulation of genelists involved in the regulation of cell migration. <i>hIGF1</i> nanoparticle treatment resulted in marked changes to transporter activity in the MNR + <i>hIGF1</i> subplacenta/decidua when compared with sham MNR. Under normal growth conditions however, <i>hIGF1</i> nanoparticle treatment decreased genelists enriched for kinase signaling pathways and increased genelists enriched for proteolysis, indicative of homeostasis. Overall, this study identified changes to the subplacenta/decidua transcriptome that likely result in inadequate trophoblast invasion and increases our understanding of pathways that <i>hIGF1</i> nanoparticle treatment acts on to restore or maintain appropriate placenta function.<b>NEW & NOTEWORTHY</b> Placental insufficiency at midpregnancy, established through moderate maternal nutrient restriction, is characterized with fewer maternal spiral arteries lined by trophoblast, shallower trophoblast invasion, and downregulation of genelists involved in the regulation of cell migration. Treatment of placenta insufficiency with a <i>hIGF1</i> nanoparticle results in marked changes to transporter activity and increases our mechanistic understanding of how therapies designed to improve fetal growth may impact the placenta.