Two distinct molecular faces of preeclampsia revealed by single-cell transcriptomics

Area of Science:

• Obstetrics and Gynecology
• Perinatal Medicine
• Molecular Biology

Background:

• Preeclampsia is a pregnancy disorder characterized by new-onset hypertension, with placental delivery required for symptom resolution.
• The placenta's role in preeclampsia pathophysiology is central, yet specific cellular impacts in different forms remain unclear.
• Understanding placental cellular function is crucial for differentiating and managing preeclampsia subtypes.

Purpose of the Study:

• To investigate and compare molecular changes across placental cell types in early- and late-onset preeclampsia.
• To identify specific cellular dysfunctions contributing to the distinct clinical manifestations of preeclampsia.
• To provide molecular evidence for distinct disease entities within preeclampsia.

Main Methods:

• Conducted a single-cell and single-nuclei transcriptomic survey.
• Analyzed placental samples from early- and late-onset preeclampsia cases and gestation-matched controls.
• Examined gene expression patterns across various placental cell types.

Main Results:

• Massive gene expression dysregulation was observed, predominantly in early-onset preeclampsia.
• Early preeclampsia showed cell-autonomous dysregulation of angiogenic factors (sFLT1/PGF) in the syncytium.
• Inflammation and stress were evident in stromal and vascular cells, with placental immune cells (Hofbauer and TREM2 macrophages) playing a key role in early preeclampsia.
• Late-onset preeclampsia exhibited minimal cellular impact on the placenta.

Conclusions:

• The study provides systematic molecular evidence supporting preeclampsia as two distinct diseases.
• Molecular dysregulation was resolved to specific cell types, offering implications for improved definition and diagnosis.
• Findings pave the way for targeted early detection and novel treatment strategies for preeclampsia.