During pregnancy, a separate, genetically different organism grows in the woman's body. This is made possible by a sophisticated interaction between the cells of the growing child, the placenta and the mother's immune system. For the first time, researchers have now mapped these processes in detail spatially and temporally. The results show how the fetal portion of the placenta alters the maternal arteries in the uterus to provide nourishment to the fetus and how the maternal immune system adapts not to reject the foreign organism.
Shortly after fertilization, a human egg begins to divide and differentiate into different cell types. The actual embryo develops from one part of the cells, another part of the cells, the so-called trophoblast, forms the child's part of the placenta, which is responsible for the supply of the embryo. These cells grow into the lining of the uterus and begin to interact with the mother's immune system. On the maternal side, the arteries change to optimally supply the embryo with blood and nutrients. This creates a three-layered placenta: a maternal and fetal part, with a space in between that is filled with maternal blood and facilitates the exchange of nutrients and waste. How exactly the mother's and child's cells work together, however, was previously unclear.
Interaction of infant and maternal cells
A team led by Shirley Greenbaum from Stanford University in California has now mapped this interaction in detail spatially and temporally for the first time. To do this, the researchers examined tissue samples from the placenta of 66 women who had made them available to scientists after they had terminated their pregnancy between the sixth and twentieth week. In these samples, Greenbaum and her team identified 588 uterine spiral arteries that were at various stages of the remodeling process. In addition, they recorded various cell markers using a specially developed imaging technique, enabling them to deduce the type, number and activity of the maternal immune cells, among other things.
"This is the first study to comprehensively map how the spiral arteries change, from not remodeled to fully remodeled," says Greenbaum's colleague Michael Angelo. It was previously known that some of the child's trophoblast cells grow in the walls of the arteries on the maternal side. But how do they get there? Do they swim against the flow of blood inside the arteries? Or do they migrate through the uterine wall? "In earlier stages of the remodeling, we found the child's trophoblast cells mainly on the outside of the blood vessels," reports the team. "Only in later stages did they also appear inside the blood vessels." This indicates that the trophoblast cells actually migrate through the uterine wall and invade the remodeling maternal arteries from the outside.
remodeling of the blood vessels
The team also found that maternal arteries do not all change at the same time, but are at different stages during the first few weeks of pregnancy. The stage of remodeling of each artery correlated with the number of infant trophoblast cells in the vicinity. While the arteries are muscular in the earlier stages, the smooth muscle breaks down as the pregnancy progresses, allowing for a high but slow flow of blood to the fetus.
When arteries are unable to expand sufficiently during early pregnancy remodeling, the mother's blood pressure rises to compensate for the lack of blood flow. This pregnancy hypertension, also called preeclampsia, can damage the mother's organs and endanger the fetus and is therefore a dreaded pregnancy complication. The new findings could help to better understand what goes wrong with preeclampsia and other complications during pregnancy. "It would be ideal if we could identify in advance who is at risk and take preventive action early on," says Angelo.
Relevance to organ transplants and cancer
According to the results, the maternal immune system also plays a major role. At the beginning of pregnancy, around the sixth to eighth week, maternal immune cells that attack foreign cells still predominate in the placenta. As the pregnancy progresses, more tolerant immune cells accumulate. "Just looking at the composition of the immune cells is a reliable clock," explains Angelo. "If we took a sample and didn't know what stage of pregnancy it was at, we could determine gestational age to within 19 days based on the types of immune cells present."
The findings could not only help explain and treat certain types of infertility, but could also be helpful for organ transplants. Here, too, it is a question of the immune system accepting foreign material. "By looking at tolerance in the context of pregnancy, we could find better ways to address long-term organ tolerance in transplantation," says Angelo. The study could also be helpful for cancer research, because many types of cancer trick the immune system with the same methods that enable the placenta to grow in the mother's body.
The study is part of the large research project Human BioMolecular Atlas Program (HuBMAP), in which various tissues and organs of the human body are mapped at the single-cell level in order to better understand the arrangement and interaction of the cells.
Source: Shirley Greenbaum (Stanford University, California, USA) et al., Nature, doi: 10.1038/s41586-023-06298-9