Scientists have just unveiled a veritable atlas of the placenta and uterus, tracing in detail how these unique tissues develop and transform throughout pregnancy to accommodate and support a growing fetus. This mapping, which covers the very beginning of gestation until delivery, makes it possible for the first time to continuously observe the evolution of the maternal-fetal interface, where a large part of the fate of the pregnancy is decided.
By drawing up this very high resolution map, the team highlighted a completely new cell subtype, which seems to only exist during pregnancy. Absent from the uterus outside of gestation, these cells appear suddenly at the very beginning of pregnancy, when the uterine lining is remodeling to envelop and nourish the embryo, explains Cheng Wang, a specialist in regenerative medicine at the University of California at San Francisco (UCSF). For Jingjing Li, lead co-author of the study relayed by Live Science, it was a moment of surprise: “We asked around, no one knew what it was.”
These newly described cells – named DSC4, for “decidual stromal cell 4” – appear to play a key role in the connection between the placenta and the maternal blood circulation. They carry receptors sensitive to cannabinoids, these molecules produced by the body but also present in cannabis, such as THC and CBD, which suggests that they could help explain why cannabis use during pregnancy is associated with reduced blood flow to the placenta, less oxygenation of the fetus and an increased risk of premature birth, low birth weight and hospitalization in neonatal intensive care.
However, it is unlikely that the sole sensitivity of these cells to cannabinoids is sufficient to account for all the risks linked to cannabis consumption in pregnant women, underlines Jingjing Li. Other mechanisms have already been identified in the medical literature, but this new cell population adds an important piece to the puzzle and justifies new targeted research. Understanding precisely how these cells react to chemical signals could ultimately help to better assess the effects of different substances on pregnancy.
A titanic job
The study, published April 8 in the journal Nature, differs from previous work which had begun to map the uterus and placenta, but only over limited periods of gestation. “The big difference is that we look at the entire timeline”summarizes Jingjing Li. The atlas incorporates samples taken between the fifth and thirty-ninth weeks of pregnancy and stored in tissue banks at UCSF and Stanford University. The researchers were thus able to continuously monitor the transformation of maternal and fetal tissues.
To build this atlas, Jingjing Li’s laboratory analyzed tissues cell by cell, focusing on placental development, one of its major areas of research. The team took real snapshots of gene and protein activity at different stages of pregnancy, while looking at chromatin accessibility, that is, how DNA is compacted in the nucleus and which genes can be activated at any given time. In total, around 1.2 million cells from the placenta and uterus were studied, including 200,000 isolated and 1 million in their original context within the tissue.
A cellular speed bump
This painstaking work revealed close links between the gene activity profile of a cell and its behavior. For example, we know that early in pregnancy, certain fetal cells invade the uterus and its large arteries to establish blood flow to the placenta; Using machine learning algorithms, the researchers were able to predict how deep a given cell would invade the uterus based on its activated genes. When this invasion process goes wrong, whether it is insufficient or excessive, it can contribute to serious complications such as preeclampsia or placenta accreta.
It is precisely on this point that the new cell type plays a role as a biological speed bump. By emitting specific signals, these DSC4 cells seem to slow down the invasion of fetal cells into maternal tissues, like a speed bump intended to prevent the process from accelerating too quickly, explains Jingjing Li. Located on the front line at the maternal-fetal interface and equipped with proteins that support this regulatory function, they appear to be critical guardians of the balance between maternal protection and the needs of the fetus.
The researchers then cross-referenced their atlas with large genetic studies focusing on preeclampsia, premature births and miscarriages. This work revealed genetic variants associated with an increased risk of complications, without always making it possible to know in which cells these genes acted. Using the new map, the team was able to identify cell types in the placenta and uterus that actually use these genes, and are therefore potentially most vulnerable to these disorders.
Despite the breadth of the data gathered, the authors insist that this is only a starting point. The study focuses on normal pregnancies, which leaves open the question of how complicated pregnancies deviate from this cellular and molecular benchmark. The team is now collaborating with clinicians to expand the map to other situations and further increase the number of cells analyzed, hoping to capture the full diversity of the cellular landscape of the gravid uterus and uncover equally surprising new findings.
