Pluripotent stem cell modeling to identify gene/environment influences on placental angiogenesis and severe fetal growth restriction

/ABSTRACT Fetal growth restriction (FGR) is the second-leading cause of perinatal morbidity and mortality. Severe cases, especially those with placental vascular changes reflected by absent or reversed umbilical artery Doppler velocimetry (FGRa/r) on ultrasound, are at high risk for perinatal death and exhibit substantially worse outcomes than FGR with preserved fetoplacental blood flow, suggesting that this flow is vital to fetal well-being. The only management option currently is delivery, with guidelines suggesting delivery no later than 34 weeks despite concomitant risks of prematurity. One consistent finding in FGRa/r is inadequate development of placental vessels through the latter half of pregnancy. This sparse vasculature compromises fetal oxygen and nutrient extraction from the maternal intervillous space, giving rise to hypoxia and acidosis, while simultaneously increasing fetal cardiac afterload. Based on a strong correlation between FGRa/r and maternal vascular malperfusion (MVM) – a histopathologic pattern representing placental injury due to defective deep placentation, inadequate uterine vascular remodeling, consequent aberrant intervillous blood flow, and hypoxia-reperfusion (H/R) injury – the conventional view is that FGRa/r is the product H/R injury. However, up to 50% of pregnancies with uncomplicated outcomes also exhibit MVM. Thus, how placental angiogenic deficiencies arise, whether they are solely a consequence of early insults resulting in H/R injury, and how fetal genetic susceptibility to in utero events impacts placental angiogenesis remain major gaps in knowledge. To address these concerns, this R21 application proposes to leverage induced pluripotent stem cell (iPSC) technology and its capacity to abrogate donor transcriptional, epigenetic, and functional signatures. Starting with control (C) and FGRa/r (F) cohorts that display MVM as an indicator of H/R exposure, we will isolate placental stromal fibroblasts (FBs), reprogram them into iPSCs, followed by differentiation into endothelial cells (iPSC- ECs). These iPSC-ECs represent placental ECs naïve to prior in utero exposures while retaining donor genome. By comparing methylomic, transcriptomic, and functional signatures between iPSC-ECs and their subject- matched, primarily isolated FBs and placental ECs, we will be able to rigorously characterize C- and F-iPSC- ECs (Aim #1) and examine the interplay between gene and environment in FGRa/r pathogenesis (Aim #2). Completion of proposed aims will provide critical foundation for (1) identifying targets that promote placental angiogenesis in spite of early in utero insults, thereby increasing surface area for maternal-fetal exchange and improving fetal cardiac function, and (2) generating patient-specific, clinically relevant models with which to test potential therapies. Project Number: 1R21HD114922-01A1 | Fiscal Year: 2025 | NIH Institute/Center: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | Principal Investigator: EMILY SU | Institution: UNIVERSITY OF COLORADO DENVER, Aurora, CO | Award Amount: $429,000 | Activity Code: R21 | Study Section: Pregnancy and Neonatology Study Section[PN] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R21HD11492201A1