Is the placenta an innocent bystander in perinatal programming?

During pregnancy, a well functioning placenta is needed to ensure appropriate growth and development of the fetus [1]. Indeed, a malfunctioning or “insufficient” placenta has been recognized as the “cause” of Intrauterine Growth Restriction (IUGR) [2], leading to decreased oxygen delivery as well as altered placental transport of nutrients, mainly amino acids and lipids, but also micronutrients such as iron and folate. A number of previous studies from our lab support this hypothesis, demonstrating a specific placental phenotype of IUGR [3], recently confirmed with decreased levels of placental Transferrin Receptor (TFRC – mediating cellular iron uptake) or of Sodium-coupled Neutral Amino acid transporter 2 (SNAT2) in IUGR versus controls [4, 5] (summarized in Tab. 1). Maternal nutritional status, diet and exposure to environmental factors are increasingly acknowledged as potentially affecting placental gene expression, thus modifying placental function. These epigenetic associations link intrauterine environment to adverse perinatal outcomes reprogramming the fetal epigenome with several mechanisms, such as methylation or miRNA, thus affecting gene expression and activity in preeclamptic (PE) and IUGR tissues [6]. Changes in miRNA expression pattern have been observed in placental tissue and associated with several pregnancy pathologies as preeclampsia (DOWN miR-21, UP miR-155, DOWN miR-223), GDM (DOWN miR-132), IUGR (DOWN miR-21, DOWN miR-210) and preterm birth (UP miR-493, UP miR-338) [7]. In this context, an active placental metabolism is crucial to support both trophoblast invasion and placentation [8]. Alterations in early implantation may lead to mismatches in oxygen (O2) delivery to different areas of the placenta, with less O2 exchange between the uterine and the umbilical circulations [9]. Mitochondrial DNA (mtDNA) copy number is positively correlated with the number of mitochondria. We have previously demonstrated altered mitochondrial content in IUGR placentas [10], with higher mtDNA levels in IUGR maternal blood [11]. Moreover, we measured the functionality of the respiratory complexes (RCC) by high-resolution respirometry (HRR), in order to assess potential alterations in placental energy metabolism [12] (summarized in Tab. 1). Preliminary observations suggest similar changes in placental mitochondria, DNA content and function of obese pregnant women. These pregnancies are characterized by low-grade inflammation and oxidative stress [13]. Moreover, dysregulated mt genes methylation (D-loop and CO1 hypomethylation) might expand our findings of higher mtDNA content in fetal cord blood of IUGR and PE [14]. These preliminary data may indeed suggest a compensatory attempt of fetuses to increase energy production through higher mtDNA content and RCC (CO1) expression, representing a further link between epigenetic changes and perinatal programming of diseases. Another issue is related to the placental hormonal function. The placenta as a source of a wide array of hypothalamic or pituitary hormones was a hot topic in the 60-70s, then neglected because of the radioactive techniques needed at that time. Steroid hormones, and in particular estrogens, are important for uterine/placental vascular adaptations to pregnancy, but also essential for trophoblast cells syncytialization in placenta. During pregnancy, the feto-placental unit is a source of estrogens through its aromatase enzyme Cytochrome P450 (CYP19) involved in estradiol (E2) production [15]. Interestingly, CYP19 levels appeared signi%cantly higher in IUGR placentas that we recently analyzed. We might speculate that the CYP19 alterations have an estrogenrelated protective action in more severe IUGR placentas, which we showed to be characterized by increased mtDNA [16]. Ongoing analyses will evaluate if these placental molecular alterations result in E2 hormone altered production. Placental mesenchymal stromal cells (p-MSCs) may also represent an interesting point to evaluate in order to understand normal and abnormal placental development. In IUGR pregnancies, p-MSCs have lower proliferation rate with earlier shift towards homogeneity than in controls. In vitro findings also demonstrate that multipotency of IUGR derived p-MSCs is restricted, as their capacity for adipocyte differentiation is increased, whereas their differentiation ability towards endothelial cell lineage is decreased (Fig. 1) [17]. These findings are indicative of changes that may also be reflected in the developing fetus (summarized in Tab. 1). The potential role for p-MSCs in pregnancy pathologies, as well as the striking mitochondrial changes involved in energy production, open new perspectives for understanding the development of the diseases and potential routes of prevention and treatment.