Scientists Discover New Cell Type Likely Linked With Preeclampsia

In creating an ambitious new cellular ‘atlas’ of the uterus and placenta in pregnancy, a group of scientists, including several funded by March of Dimes, have identified a new cell type that is unique to pregnancy and may hold the key to understanding two of pregnancy’s most dangerous complications: preeclampsia and placenta accreta.

The research team found that the new decidual stromal cell subtype, or DSC4, seen in the uterus of pregnant women, plays a vital role in the foundation of a healthy pregnancy: it regulates the proper invasion of fetal cells into maternal uterine tissue during placental development, one of pregnancy’s most complex and important processes.

As such, researchers, who recently published their findings in the journal Nature, think the cell type may be instrumental in regulating fetal cell invasiveness, whose dysregulation is often associated with preeclampsia, marked by shallow placental implantation, and placenta accreta, marked by implantation that is too deep.

One of the cell type’s most crucial roles in pregnancy, the team discovered, is to act as a regulatory “speed bump” that suppresses the invasiveness of fetal trophoblast cells at the initial stage of fetal cell invasion into the uterine wall, said study first author Dr. Cheng Wang, who is a specialist scientist at the University of California, San Francisco.

“This uterine cell type appears to act as a local gatekeeper that tunes the invasive potential of fetal trophoblast cells as they penetrate maternal tissue,” said Dr. Wang. “It represents a maternal uterine mechanism for constraining and calibrating trophoblast invasion at the maternal–fetal interface.”

He added that this cell’s restraining function is context-dependent; controlled restraint may be necessary for normal placental development, whereas excessive or mistimed restraint could impair trophoblast invasion and contribute to pregnancy complications. Further investigating the cell’s role in preeclampsia is a “major focus of our ongoing work,” he said.

Dr. Wang works alongside senior study author Dr. Jingjing Li, an Associate Professor at the University of California, San Francisco’s Department of Neurology and a close collaborator of investigators at the March of Dimes Prematurity Research Center (PRC) at Stanford.

The role of March of Dimes scientists in the research can be traced back to the initiation of the first March of Dimes PRCs, sparking collaborations between Washington University School of Medicine professor Dr. Sarah England and two scientists at the March of Dimes PRC at Stanford: lead investigator Dr. David Stevenson and his colleague Dr. Gary Shaw. The partnership between the scientists helped Dr. Li conceive the project. Drs. England, Stevenson, and Shaw met regularly with Dr. Li and his team to help shape the research as it progressed.

The discovery of the new family of cells occurred while Drs. Wang, Li, and team were analyzing a sophisticated technical atlas of more than 1 million uterine and placental cells — matched with high-risk genetic variants from large-scale genome-wide association studies — they had created to identify “vulnerable” cell types displaying cell-type-specific associations with genetic risk of the main pregnancy complications. The cells were derived from healthy pregnancies as reference and collected by teams at Stanford and UCSF.

“The main players in this map are the two distinct families of cells, maternal and fetal, that must learn to coexist for a healthy pregnancy,” Dr. Wang said. “The trophoblasts are the primary fetal explorers that safely invade the mother’s uterus, anchor the placenta, and remodel maternal blood vessels, while the maternal cells are like the hosts, and those include stromal cells, vascular endothelial cells and resident immune cells.”

“This atlas allowed us to see exactly where these main players are located, which genes they are expressing, and how their physical proximity to one another shifts as pregnancy progresses, with the ultimate goal of identifying specific cell types through which genetic risk for pregnancy disorders is exerted.”

In addition to the discovery of the new cell family that regulates fetal cell invasion, the team identified other cell types that are vulnerable to the development of preeclampsia and spontaneous preterm birth.

“Our data suggest that the cells most vulnerable in preeclampsia are those directly involved in maternal spiral artery remodeling,” Dr. Wang said, “pointing to preeclampsia as a disorder of failed cellular coordination at the maternal–fetal interface, particularly during the vascular remodeling process required to establish a healthy placenta.”

For spontaneous preterm birth, the team identified a specific epithelial cell subtype as a possible actor of genetic risk that they plan to further study.

Dr. Wang added that because the healthy cells were matched with whole-genome risk variants, the resulting findings about vulnerable cell types apply to all pregnant women, not just those that carry specific genetic risk for pregnancy complications.

“If the biological processes within these vulnerable cells fail due to environmental or other non-genetic factors, the resulting complications will likely follow the same path we discovered through genetics,” he said.

Immediate next steps include probing the link between preeclampsia and the new cell type, as well as populating the atlas with cells from pregnancies with preeclampsia or spontaneous preterm birth to compare the behavior of cells in healthy and unhealthy pregnancies and home in on disease processes.

The team’s ultimate goal, Dr. Wang said, is to use the wealth of information they uncover about vulnerable placental and uterine cell populations to develop prediction tools that can offer early identification of women at risk of adverse pregnancy outcomes, and to pinpoint therapeutics that may manipulate vulnerable cell populations before disease processes progress and a pregnancy goes awry. In the case of cells vulnerable to preeclampsia, Dr. Wang said, one possible way to do this would be to reverse-engineer cells associated with poor placental invasion in vitro before returning them back to the mother’s body.

“The broader hope is that once the most vulnerable cell types are identified,” he said, “we can begin to design strategies to protect, stabilize, or reprogram them before pathology fully develops.”