Summary: In a landmark study, scientists have created the most detailed map ever of the “maternal-fetal interface”—the critical biological border where a mother’s uterus meets the baby’s placenta.
By analyzing over 1.2 million cells using single-cell and spatial technology, researchers discovered entirely new cell types and identified the specific genetic “command centers” that fail during preeclampsia, miscarriage, and preterm birth. This atlas provides a molecular blueprint that could lead to the first truly targeted treatments for pregnancy complications.
Key Facts
- The “Cannabis” Connection: Researchers discovered a new maternal cell type that regulates how the placenta attaches to the uterus. These cells contain a cannabinoid receptor; when exposed to cannabis molecules, they restrict placental invasion, offering a biological explanation for why cannabis use is linked to poor pregnancy outcomes.
- Preeclampsia Unmasked: The study found that preeclampsia—a dangerous spike in blood pressure—is likely caused by a breakdown in communication between maternal and fetal cells that are supposed to “remodel” uterine blood vessels to increase blood flow.
- Massive Data Scale: The team analyzed 200,000 individual cells and mapped nearly 1 million more in their precise anatomical locations to see exactly who “talks” to whom in the womb.
- Mapping Risk: By integrating data from 10,000 patients, the team matched genetic risk signals for preterm birth and miscarriage to specific cell types, moving beyond general theories to pinpoint exact cellular culprits.
- Essential Boundary: The maternal-fetal interface is a temporary organ that forms just one week after fertilization. It is responsible for feeding the fetus while protecting the mother’s immune system from attacking the “foreign” DNA of the baby.
Source: UCSF
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, PhD, 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, PhD, 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. Exposure to cannabinoid molecules caused them to further restrict placental cell invasion.
“Population studies have linked cannabis use during pregnancy to poorer outcomes,” said Cheng Wang, PhD, 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.
Key Questions Answered:
A: Think of the placenta like a tree’s roots. If it doesn’t “dig” deep enough into the mother’s uterine tissue, it can’t tap into her blood supply effectively. This study found a specific new cell type that acts as a gatekeeper for this process; if these cells are too restrictive (as they are when exposed to cannabinoids), the baby doesn’t get the nutrients it needs.
A: Until now, we didn’t know which specific cells were failing during a miscarriage. By mapping the genetic risk signals of 10,000 patients onto this new 3D atlas, doctors can now see which cell “states” are the most fragile. This allows researchers to develop drugs that target those exact cells to strengthen the connection between mother and baby.
A: We knew preeclampsia involved high blood pressure, but we didn’t know it was a “communication” error. The study shows that maternal and fetal cells have to “talk” to each other to widen the mother’s blood vessels. In preeclampsia, this conversation breaks down, and the vessels stay narrow, causing the mother’s blood pressure to skyrocket as her body tries to force blood through to the baby.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this genetics and neurodevelopment research news
Author: Laura Kurtzman
Source: UCSF
Contact: Laura Kurtzman – UCSF
Image: The image is credited to Neuroscience News
Original Research: Closed access.
“Single-Cell Spatiotemporal Dissection of the Human Maternal–Fetal Interface” by Serena Tamura, Andrew D. Nelson, Perry W. E. Spratt, Elizabeth C. Hamada, Xujia Zhou, Henry Kyoung, Zizheng Li, Coline Arnould, Vladyslav Barskyi, Beniamin Krupkin, Kiana Young, Jingjing Zhao, Stephanie S. Holden, Atehsa Sahagun, Caroline M. Keeshen, Congyi Lu, Roy Ben-Shalom, Sunrae E. Taloma, Selin Schamiloglu, Ying C. Li, Lia Min, Paul M. Jenkins, Jen Q. Pan, Jeanne T. Paz, Stephan J. Sanders, Navneet Matharu, Nadav Ahituv & Kevin J. Bender. Nature
DOI:10.1038/s41586-025-09522-w
Abstract
Single-Cell Spatiotemporal Dissection of the Human Maternal–Fetal Interface
Most neurodevelopmental disorders with single gene diagnoses act via haploinsufficiency, in which only one of the two gene copies is functional. SCN2A haploinsufficiency is one of the most frequent causes of neurodevelopmental disorder, often presenting with autism spectrum disorder, intellectual disability and, in a subset of children, refractory epilepsy.
Here, using SCN2A haploinsufficiency as a proof-of-concept, we show that upregulation of the existing functional gene copy through CRISPR activation (CRISPRa) can rescue neurological-associated phenotypes in Scn2a haploinsufficient mice.
We first show that restoring Scn2a expression in adolescent heterozygous Scn2a conditional knock-in mice rescues electrophysiological deficits associated with Scn2a haploinsufficiency (Scn2a+/−).
Next, using an adeno-associated virus CRISPRa-based treatment in adolescent mice, we show that we can correct intrinsic and synaptic deficits in neocortical pyramidal cells, a major cell type that contributes to neurodevelopmental disorders and seizure aetiology in SCN2A haploinsufficiency.
Furthermore, we find that systemic delivery of CRISPRa protects Scn2a+/− mice against chemoconvulsant-induced seizures. Finally, we also show that adeno-associated virus CRISPRa treatment rescues excitability in SCN2A haploinsufficient human stem-cell-derived neurons.
Our results showcase the potential of this therapeutic approach to rescue SCN2A haploinsufficiency and demonstrates that rescue even at adolescent stages can ameliorate neurodevelopmental phenotypes.
