Placental cell type deconvolution reveals that cell proportions drive preeclampsia gene expression differences

Area of Science:

• Reproductive biology
• Genomics
• Computational biology

Background:

• Preeclampsia is a major cause of adverse pregnancy outcomes.
• Placental cellular heterogeneity in preeclampsia is poorly understood.
• Bulk gene expression studies limit mechanistic insights into preeclampsia.

Purpose of the Study:

• To create a comprehensive placental cell type deconvolution reference.
• To investigate the impact of cellular heterogeneity on gene expression in preeclampsia.
• To identify cell type-specific alterations in preeclampsia.

Main Methods:

• Generated single-cell RNA-sequencing data from placental villous tissue.
• Integrated data to build a reference of 19 fetal and 8 maternal cell types.
• Deconvoluted eight preeclampsia microarray studies using the reference.

Main Results:

• Preeclampsia associated with increased extravillous trophoblasts and decreased mesenchymal/Hofbauer cells.
• Cellular composition adjustment removed 1154 differentially expressed genes.
• Downregulation of mitochondrial and ribosome biogenesis pathways persisted after adjustment.
• Cellular composition explained significant portions of FLT1, LEP, and ENG overexpression.

Conclusions:

• Placental cellular heterogeneity significantly contributes to gene expression changes in preeclampsia.
• Direct alterations in mitochondrial and ribosome biogenesis pathways occur in preeclampsia.
• This deconvolution reference enables cell type-aware research into placental dysfunction and adverse birth outcomes.