ABOVE: Maternal-fetal communication across the placenta is important for many obstetrical processes, including preterm labor and birth. © iStock, magicmine

Parents often celebrate their children’s communication milestones as they grow up, but long before babies babble, their cells have a lot to say. During pregnancy and labor, cellular communication across the placenta is a critical yet mysterious process.1,2 Although scientists have uncovered several signaling pathways involved in this process, how maternal-fetal crosstalk regulates labor’s timing remains poorly understood. 

“How do you know whether a mother will deliver preterm or not? Well, the short answer is, we don't know,” said Nardhy Gomez-Lopez, an immunologist who studies obstetrics and gynecology at Washington University in St. Louis. Gomez-Lopez studies birth, also called parturition, through the lens of cellular changes in the maternal-fetal interface, which includes immune and nonimmune cells in the placenta.

Nardhy Gomez-Lopez (left) and Valeria Garcia-Flores (right)
Nardhy Gomez-Lopez (left) worked with Valeria Garcia-Flores (right) to investigate maternal-fetal cell communication’s role in labor.
Perinatology Research Branch, Detroit Medical Center 

In a recent study published in Science Translational Medicine, Gomez-Lopez collaborated with researchers and clinicians to create a single-cell atlas of the placenta during labor.3 The team revealed labor-specific transcriptional signatures that were also present in subsets of preterm labor patients, adding new insight to the maternal and fetal pathways that govern term and preterm birth.

The team investigated which cellular interactions facilitate previously established inflammatory signaling pathways during labor by performing single-cell RNA-sequencing (RNA-seq) on placental and extraplacental tissues donated by patients who delivered with or without spontaneous labor. The researchers genotyped each cell’s origin to identify known and new cell types involved in labor.

“The placenta is a fetal organ, but it has maternal cells infiltrating,” Gomez-Lopez explained. “Because I was working with experts in the field of maternal-fetal communication, my thought was, we need to figure out which cells are mom’s and which cells are fetal because they may have different contributions.”

In extraplacental membranes, fetal stromal cells and maternal decidual cells and macrophages showed the greatest changes in gene expression pathways such as apoptosis, cell migration, and inflammation, while immune function pathways in fetal macrophages and maternal monocytes were most affected in the placental tissue.

Gomez-Lopez and her team integrated their single-cell RNA-seq data with other bulk placenta and maternal blood transcriptomic datasets. They detected labor-specific signatures in circulation during early gestation, which were also present in a subset of patients who experienced spontaneous preterm birth. Their integrated datasets revealed that placental signatures may help predict which preterm labor episodes lead to parturition.

Medical illustrations of the fetal and maternal placental surfaces.
Maternal-fetal communication across the placenta is important for many obstetrical processes, including preterm labor and birth.
© iStock, Sakurra

“It's a really exciting time for placenta development now that we have advances in things like single-cell RNA sequencing, and there are a lot of datasets in the field that people can integrate with their new datasets to increase the number of samples and increase the power to their studies,” said Norah Fogarty, a placental developmental biologist at King’s College London who was not involved in this study. “The parts of this study that stood out were the different types of samples they had. They had healthy, uncomplicated pregnancies; they had pregnancies that had preterm deliveries where there were no signs of infection and then ones where there were signs of infection,” Fogarty said. “It wasn't a massive sample size, but it was a good place to start.”

The team’s observations suggest that a blood test may one day predict when preterm labor is destined for delivery, but much work remains to validate these potential biomarkers. “To be rolling out biomarkers for testing in people at risk of developing preterm birth, you are going to have to have some mechanistic insights, and the way to do that, I think, at this stage of pregnancy, is going to have to involve in vitro models of some sort,” Fogarty said. “With this dataset, we are informed a little bit about the relevant cell types that we would want to capture in an in vitro model.”

Gomez-Lopez also sees this study as a stepping stone rather than a destination for maternal-fetal crosstalk’s role in labor. She hopes that the research community is on the right track toward healthier perinatal outcomes. “There is a need to do more investigations about how we can utilize this information or this concept to better reduce adverse perinatal outcomes, and I am not just talking about preterm birth. The placenta is important for many obstetrical diseases. So, I think it is an opportunity, but obviously it is a proof-of-concept investigation.”