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Pregnancy-Related Immune Changes Revealed by Single-Cell Placenta Sequencing

NEW YORK (GenomeWeb) – A UK-led team has used single-cell RNA sequencing to map expression profiles in the placenta, focusing on the decidua tissue that forms from the lining of the uterus and placental trophoblast tissue from the fetus that interacts with maternal cells.

"For the first time ever, we have been able to see which genes are active in each cell in the decidua and the placenta, and have discovered which of these could modify the maternal immune system," co-first author Roser Vento-Tormo, a post-doctoral researcher in co-senior author Sarah Teichmann's lab at the Wellcome Sanger Institute, said in a statement. "The fetal cells from the placenta communicate with the mother's immune cells to ensure the placenta implants correctly. This allows the fetus to grow and develop normally."

Vento-Tormo and her colleagues teased out placental cell interactions and interactions at the interface of maternal and fetal tissues using microscopy and transcriptomes generated for roughly 70,000 individual cells from first trimester samples, including 11 decidua samples and five placentas, and half a dozen matched normal blood samples. They also used a statistical approach to interpret communication between cells profiled with a 10x Genomics Chromium droplet system, Illumina sequencing, and the Smart-seq2 protocol, and developed an open repository to bring the data together, trace cell-specific expression, and predict molecular interactions between different cell types.

The results, published online today in Nature, revealed ways in which pregnancy reshapes maternal immune activity in the developing placenta, leading to changes in both innate and adaptive arms of the immune system at sites that might otherwise interfere with the placenta or the uterus — an anti-inflammatory and anti-immune environment that shares some features with tissues surrounding some tumors.

By untangling such interactions, the team hopes to lay the foundation for future studies of pregnancy complications such as pre-eclampsia, still birth, or miscarriage. The so-called Human Cell Atlas of early pregnancy "gives us a reference map of this vital initial phase of development," Teichmann, co-chair of the Human Cell Atlas organizing committee, said in a statement.

The results "will transform our understanding of healthy development, and is helping us understand how the placental and maternal cells communicate with each other to support pregnancy," she added. "This will shed light on disorders of pregnancy, and could also help understand pathways that cancer cells exploit." 

For a related study published in Science Advances last month, researchers from Rockefeller University, Columbia University, and Albert Einstein College of Medicine applied single-cell RNA-seq to 14,341 human placental villous cells from eight samples and nearly 6,800 individual cells from six decidua samples collected during the first six to 11 weeks of gestation.

Using that data, the researchers found 20 main cell types and many more subtypes in these tissues, and highlighted some of the key regulatory features, cellular interactions, and cell subtype dynamics that characterized the first-trimester placenta tissue cells. For example, they saw hints of a transition from anti-inflammatory activity by extravillous trophoblast cells early in pregnancy to trophoblast cells that were more invasive as pregnancy progressed. 

That study's authors noted that their work "provides a blueprint to further the understanding of the roles of these cells in the placenta and decidua for maintenance of early gestation as well as pathogenesis in pregnancy-related disorders."