Spatially resolved fetal and maternal cell contributions to severe preeclampsia across gestation.

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.