The biological connection between a pregnant woman and her developing baby has been mapped in unprecedented detail by UC San Francisco scientists, revealing new cell types and insights into conditions such as preeclampsia, preterm birth, and miscarriage.
Using advanced single-cell and spatial tools, the researchers analyzed about 200,000 individual cells and compared them with nearly 1 million cells in their original positions within the uterine and placental tissue. This enabled them to identify different cell types, track how they develop, and see how they are linked to pregnancy complications.
“This work gives us a much clearer picture of this critical region than ever before,” said Jingjing Li, Ph.D., associate professor in UCSF’s Department of Neurology and the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research. He is the senior author of the study, published in Nature on April 8.
The maternal-fetal interface is a temporary but essential structure composed of uterine and placental cells that forms about a week after fertilization and lasts throughout pregnancy. It supports fetal growth while maintaining the mother’s health. Its complexity has long limited scientists’ ability to study how healthy pregnancies develop and why complications arise.
“By examining this tissue cell by cell across pregnancy, we can begin to understand both normal development and what may go wrong,” said Susan J. Fisher, Ph.D., professor of Obstetrics, Gynecology and Reproductive Sciences at UCSF and co-leader of the study.
Discovery of a new cell type
The atlas revealed a previously unknown maternal cell type located where fetal placental cells first enter the uterus. These cells appear to regulate how deeply placental cells invade uterine tissue, a process that is essential for establishing blood flow to the fetus. The researchers found that these cells carry a cannabinoid receptor, meaning cannabis molecules can latch onto them. Exposure to cannabinoid molecules, like those found in cannabis, caused them to further restrict placental cell invasion.
“Population studies have linked cannabis use during pregnancy to poorer outcomes,” said Cheng Wang, Ph.D., the study’s first author. “This cell type may help explain the biological basis of that association.”
To understand how complications arise, the team integrated genetic data from more than 10,000 patients. They mapped genetic risk signals for conditions including preterm birth, preeclampsia, and miscarriage onto regulatory regions of DNA that control gene activity. This approach allowed the researchers to identify the specific cell types and states most strongly associated with each condition.
The team then focused on preeclampsia, a potentially life-threatening disorder marked by sudden high blood pressure. They found that the most affected cell types are involved in remodeling the mother’s uterine blood vessels, a process required to supply adequate blood to the placenta. The findings suggest that preeclampsia may result from disrupted communication between maternal and fetal cells that normally coordinate this process.
Having established a detailed map of healthy pregnancies, the researchers plan to study complicated pregnancies to identify potential targets for treatment.
Authors: Other UCSF authors include Yan Zhou, MD; Yuejun Jessie Wang, PhD; Zhida Luo, PhD; Tara I. McIntyre, PhD; Marisa E. Schwab, MD; Brittany R. Davidson; Gabriella C. Reeder; Juan M. Gonzalez, MD, PhD; Robert Blelloch, MD, PhD; Alexis J. Combes, PhD; Linda C. Giudice, MD, PhD; Adrian Erlebacher, MD, PhD; and Tippi C. MacKenzie, MD.
Funding: Chan Zuckerberg Initiative (the Silicon Valley Community Foundation, DAF2021-239932, and DAF2020-217686) and National Institute of General Medical Sciences (R35GM142983).
