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

作者：Kyle A. Campbell, Justin A. Colacino, Muraly Puttabyatappa, John Dou, Elana R. Elkin, Saher Sue Hammoud, Steven E. Domino, Dana C. Dolinoy, Jaclyn M. Goodrich, Rita Karen Loch-Caruso, Vasantha Padmanabhan, Kelly M. Bakulski · 发表于：Communications Biology · 年份：2023 · DOI：10.1038/s42003-023-04623-6 · 被引用次数：80 · 研究领域：Pregnancy and preeclampsia studies、Birth, Development, and Health、Single-cell and spatial transcriptomics

Abstract The placenta mediates adverse pregnancy outcomes, including preeclampsia, which is characterized by gestational hypertension and proteinuria. Placental cell type heterogeneity in preeclampsia is not well-understood and limits mechanistic interpretation of bulk gene expression measures. We generated single-cell RNA-sequencing samples for integration with existing data to create the largest deconvolution reference of 19 fetal and 8 maternal cell types from placental villous tissue ( n = 9 biological replicates) at term ( n = 40,494 cells). We deconvoluted eight published microarray case–control studies of preeclampsia ( n = 173 controls, 157 cases). Preeclampsia was associated with excess extravillous trophoblasts and fewer mesenchymal and Hofbauer cells. Adjustment for cellular composition reduced preeclampsia-associated differentially expressed genes (log 2 fold-change cutoff = 0.1, FDR < 0.05) from 1154 to 0, whereas downregulation of mitochondrial biogenesis, aerobic respiration, and ribosome biogenesis were robust to cell type adjustment, suggesting direct changes to these pathways. Cellular composition mediated a substantial proportion of the association between preeclampsia and FLT1 (37.8%, 95% CI [27.5%, 48.8%]), LEP (34.5%, 95% CI [26.0%, 44.9%]), and ENG (34.5%, 95% CI [25.0%, 45.3%]) overexpression. Our findings indicate substantial placental cellular heterogeneity in preeclampsia contributes to previously observed bulk gene expression differences. This deco...