Yara E. Sánchez-Corrales, Theodoros Xenakis, Jose J Moreno-Villena, Leysa Forrest, Neil J. Sebire, Elizabeth C. Rosser, L C Wedderburn, Sergi Castellano, Sara Hillman
5 min
The molecular and cellular pathophysiology of preeclampsia remains poorly understood, particularly regarding how tissues beyond the placenta contribute to the disease. The researchers investigated the fetal-maternal interface to distinguish fetal and maternal contributions to early and late presentations of severe preeclampsia across gestation. To achieve this, they recruited a cohort of 20 donors spanning 25 to 37 gestational weeks, comprising 10 severe preeclampsia cases and 10 gestationally matched controls. They performed single-cell RNA sequencing across multiple tissues—including the placental villi and basal plate, chorioamniotic membranes, myometrium, and peripheral blood mononuclear cells—alongside Visium and Xenium spatial transcriptomics to maintain spatial context.
Accounting for gestational age using a generalized linear model, the analysis demonstrated that unique molecular contributions to severe preeclampsia are substantial across the fetal-maternal interface. In the placental villi, syncytiotrophoblasts and cytotrophoblasts exhibited coordinated single-cell and spatial molecular signatures of hypoxia, angiogenic imbalance, fibrosis, and aberrant metabolism. The study further mapped extravillous trophoblasts across the decidua basalis and myometrium, finding both a reduced density and a decreased depth of invasion in early severe preeclampsia. Furthermore, endothelial extravillous trophoblasts showed a significant reduction in their associations as nearest neighbors with maternal endothelial cells, accompanied by down-regulated cell adhesion markers.
Beyond the placenta, the researchers uncovered profound maternal immune dysregulation extending into the myometrium and chorioamniotic membranes. These included altered macrophage activity, mitochondrial dysfunction, and active interferon signaling, which likely contribute to systemic inflammation and endothelial dysfunction in the mother. Because these tissue- and cell-specific responses are prominent in early gestational disease, they offer concrete targets for potential therapeutic intervention that could eventually alter the poor prognosis associated with severe preeclampsia.
The molecular and cellular pathophysiology of preeclampsia remains poorly understood, but it is increasingly clear that in addition to the placenta, other tissues of the fetal-maternal interface advance the disease. Here, we distinguish fetal and maternal contributions to the early and late presentation of severe preeclampsia by interrogating, across time and space, tissues and cell types relevant to the disease. Accounting for gestational age in a third trimester preterm cohort, we find single-cell and spatial molecular signatures of concerted hypoxia, angiogenic imbalance, fibrosis, and aberrant metabolism in the placenta. In addition, we report maternal immune signatures such as mitochondrial dysfunction and interferon signaling extending to the myometrium and chorioamniotic membranes, likely contributing to the systemic inflammation and endothelial dysfunction in the mother, with impaired fetal cell interactions with endothelial cells in the myometrium contributing to it. These tissue- and cell-specific responses are potential targets for therapy, with their prompt consideration in early gestational disease likely beneficial because of its aggravated molecular presentation. Thus, timely intervention during gestation could change the extremely poor prognosis of severe preeclampsia.
Sam: Not quite. Their gene activity shifts in a telling way. They dial down the molecules that help cells stick together and anchor into vessel walls. And at the same time, they ramp up signals that promote inflammation. So they lose the ability to do their structural job, and they start stirring up an immune response instead.
Alex: Does that disruption stay confined to the uterine wall, or does it spread?
Sam: It spreads. The same pattern of dysfunction appears in the membranes surrounding the fetus. And when researchers looked at the mother's own immune cells throughout these tissues — including natural killer cells and a type of immune cell called a macrophage — they found something consistent: the cells' internal energy-producing machinery was under serious stress.
Alex: What does that mean in practical terms?
Sam: Think of it like this. Every cell has tiny power stations inside it that convert fuel into energy. In these immune cells, those power stations are misfiring, producing harmful byproducts as a side effect. That cellular stress then triggers a specific immune alarm — the same kind the body normally raises during a severe viral infection.
Alex: So the mother's immune system is essentially behaving as though it's fighting off a serious virus?
Sam: That's what the pattern looks like. And what makes this particularly significant is that this inflammatory alarm signal is detectable not just in the local tissues, but in the mother's circulating blood. The macrophages caught in this environment also start behaving differently depending on where they are — those near the placenta begin activating genes associated with cell death and scarring.
Alex: So the damage compounds across multiple tissue types simultaneously.
Sam: That's the core finding. Severe preeclampsia isn't a localized placental problem that happens to have some knock-on effects. It appears to trigger a coordinated, system-wide immune and metabolic breakdown across the entire interface between mother and fetus.
Alex: Which would explain why monitoring the placenta alone isn't enough to catch the full picture.
Sam: Precisely. And it points toward a potential clinical application. If these stress signals — particularly the ones related to cellular energy dysfunction — appear in the mother's blood early in pregnancy, they might eventually serve as warning markers that clinicians could screen for before the condition becomes life-threatening.
Alex: That's a meaningful possibility. Are there caveats?
Sam: Several worth noting. The donor cohort, while detailed, is relatively small — which limits the ability to detect rare cell types that might also be playing a role. There's also a technical constraint: the process of breaking tissue apart to study individual cells can damage or exclude fragile cell populations, so some players in this story may be underrepresented in the data.
Alex: So the map is detailed, but it may not yet be complete.
Sam: That's a fair way to put it. The next step would be validating these potential markers in much larger patient groups before they could realistically inform clinical practice. But as a foundation for understanding how this disease operates — and where to look for early signs — this study offers a notably more complete picture than what we had before.
Alex: Thanks for walking us through it. Thanks for listening to ResearchPod.