Summary: A team of researchers at the University of California, San Francisco (UCSF) has produced the most detailed molecular and cellular map to date of the maternal–fetal interface—the transient, essential boundary where a pregnant woman’s uterus and the developing placenta meet.
By applying advanced single-cell and spatial profiling techniques to more than 1.2 million cells, the investigators identified previously unknown cell types, traced developmental trajectories across pregnancy, and pinpointed the genetic regulatory elements that malfunction in conditions such as preeclampsia, miscarriage, and preterm birth. This comprehensive atlas creates a precise blueprint for the cells and molecular pathways that maintain a healthy pregnancy and offers a roadmap to develop targeted therapies for pregnancy complications.
Key Facts
- New maternal cell type discovered: Researchers identified a maternal cell population at the point where fetal placental cells first contact uterine tissue. These cells appear to regulate the depth of placental invasion, a critical step for establishing sufficient blood supply to the fetus.
- Link to cannabinoids: The newly discovered maternal cells express a cannabinoid receptor. Exposure to cannabinoid molecules reduced placental invasion in experimental assays, providing a plausible biological mechanism for epidemiological findings that associate prenatal cannabis use with adverse pregnancy outcomes.
- Preeclampsia mechanism revealed: The study implicates disrupted communication between specific maternal and fetal cell types that remodel uterine blood vessels. This breakdown in cellular signaling may underlie the inadequate vessel remodeling and high blood pressure characteristic of preeclampsia.
- Large-scale, high-resolution data: The team profiled about 200,000 individually sequenced cells and spatially mapped nearly 1 million additional cells in their anatomical context, allowing researchers to see precisely which cells interact and how their locations influence function.
- Genetic risk mapped to cell types: By integrating genetic data from approximately 10,000 patients, investigators connected risk loci for preterm birth, miscarriage, and related conditions to the regulatory DNA regions of the specific cell types and cellular states most likely responsible for those outcomes.
- The maternal–fetal interface is a temporary organ: Forming roughly one week after fertilization and persisting throughout pregnancy, this interface provides nutrients to the embryo while preventing the maternal immune system from attacking fetal tissues.
Source: UCSF
Overview
UCSF scientists used integrated single-cell sequencing and spatial transcriptomics to create an atlas of the human maternal–fetal interface at unprecedented resolution. Their work captures cellular diversity, developmental dynamics, and spatial relationships across gestation, permitting the identification of cell types and molecular pathways linked to healthy pregnancy as well as to complications such as preeclampsia, miscarriage, and preterm birth.
“This atlas gives us a far clearer picture of the maternal–fetal boundary than previously possible,” said Jingjing Li, PhD, associate professor in UCSF’s Department of Neurology and a senior author of the study. Published in Nature, the work combines cell-level sequencing with spatial mapping to show how cells are organized and communicate in situ.
The maternal–fetal interface is composed of both uterine and placental cell types that coordinate to deliver nutrients, oxygen, and immunological tolerance to the developing fetus. Its structural and cellular complexity has historically hindered efforts to understand the precise mechanisms that support healthy pregnancies or lead to complications.
“By profiling this tissue cell by cell across pregnancy, we can begin to distinguish normal developmental programs from the cellular failures that cause disease,” 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 maternal cell population positioned where fetal placental cells first invade the uterus. These gatekeeper-like cells regulate the extent of placental penetration into maternal tissue. Importantly, they express a cannabinoid receptor, and experimental exposure to cannabinoid molecules made these cells more restrictive. That observation offers a possible mechanistic link between prenatal cannabis exposure and poorer pregnancy outcomes reported in population studies.
To connect cellular findings with clinical risk, the researchers mapped genetic variants from over 10,000 patients onto the atlas. By assigning disease-associated regulatory regions to specific cell types and states, they could identify which cells are most likely to mediate genetic risk for conditions such as preterm birth, miscarriage, and preeclampsia.
Focusing on preeclampsia, the team found that the cell types most affected are involved in remodeling uterine blood vessels to increase maternal blood flow to the placenta. The data indicate that inadequate vessel remodeling stems from disrupted signaling between maternal and fetal cells, offering a clearer explanation of the pathophysiology behind this dangerous hypertensive disorder.
With a detailed reference map of healthy pregnancies established, the research group plans to apply the same single-cell and spatial approaches to samples from complicated pregnancies. Those comparisons should reveal therapeutic targets by highlighting the exact cells and molecular programs to correct.
Key Questions Answered:
A: Placental invasion functions like a root system: it guides the placenta to reach and tap into the mother’s blood supply. If invasion is insufficient, the placenta cannot access enough maternal blood to support fetal growth. The study identifies a maternal cell population that acts as a gatekeeper for invasion; if these cells are overly restrictive—as they may be after cannabinoid exposure—fetal nutrition and growth can be compromised.
A: Previously, the precise cell types failing in many miscarriages were unknown. By overlaying genetic risk profiles from thousands of patients onto a three-dimensional cellular atlas, researchers can now see which specific cell states are most vulnerable. That information enables the design of therapies targeted to those cells to stabilize the maternal–fetal connection.
A: The study reframes preeclampsia as a failure of intercellular communication. Maternal and fetal cells normally coordinate to widen uterine blood vessels; when that signaling fails, vessels remain narrow, reducing placental blood flow and causing maternal hypertension as the body compensates.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- The journal paper was reviewed in full.
- Additional context was provided by editorial staff.
About this genetics and neurodevelopment research news
Author: Laura Kurtzman
Source: UCSF
Contact: Laura Kurtzman – UCSF
Image credit: Neuroscience News
Original Research: Closed access. “Single-Cell Spatiotemporal Dissection of the Human Maternal–Fetal Interface” by Serena Tamura et al., published in Nature. DOI: 10.1038/s41586-025-09522-w
Abstract
Single-Cell Spatiotemporal Dissection of the Human Maternal–Fetal Interface
Most neurodevelopmental disorders caused by single-gene variants act through haploinsufficiency, in which only one functional copy of a gene remains. SCN2A haploinsufficiency is a common genetic cause of neurodevelopmental disorders, associated with autism spectrum disorder, intellectual disability, and, in some children, treatment-resistant epilepsy.
Using SCN2A haploinsufficiency as a proof of principle, researchers show that upregulating the remaining functional gene copy through CRISPR activation (CRISPRa) can rescue neuronal and physiological phenotypes in model systems. Restoring Scn2a expression in adolescent heterozygous conditional knock-in mice corrected electrophysiological deficits linked to Scn2a haploinsufficiency (Scn2a+/−).
An adeno-associated virus-based CRISPRa treatment delivered to adolescent mice corrected intrinsic and synaptic defects in neocortical pyramidal neurons, a cell type central to neurodevelopmental disorders and seizure susceptibility in SCN2A haploinsufficiency. Systemic CRISPRa delivery protected Scn2a+/− mice from chemoconvulsant-induced seizures. In parallel, CRISPRa rescued excitability in SCN2A haploinsufficient human stem-cell-derived neurons.
These results demonstrate the potential of CRISPRa to upregulate the healthy gene copy and ameliorate neurodevelopmental phenotypes, even when treatment is initiated during adolescence.