It is a physiological storm, orchestrated at the border between the placenta and the uterine lining. Labour, the first stage of childbirth during which the cervix gradually dilates and disappears, is triggered by a series of cellular, immune and vascular mechanisms. But this process does not depend solely on the mother's body: the fetus itself influences its onset by releasing chemical signals that stimulate the production of hormones, such as oxytocin, which are key to uterine contractions. But how does this ballet between a mother and her unborn child come together?
While the existence of maternal-fetal "communication" had long been suspected, the contributions of each cell type to this dialogue, whether maternal or fetal in origin, remained largely unknown. However, several studies suggest that a disruption of these interaction pathways can lead to premature births. To better predict such events, a team of American researchers has generated the first comprehensive atlas of the feto-maternal cellular pathways involved in the induction of labour. The findings appeared in Science Translational Medicine. This, their authors hope, will better understand what is at stake just before a birth.
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The placenta and its cell populations
To generate such a map, the scientists studied 42 placentas collected during childbirth and 159 blood samples taken from women who had given birth, 100 of them prematurely. They sought to identify the types of maternal and fetal cells most affected by induction of labour. What is new is that they relied on an advanced genetic sequencing method called "single-cell RNA sequencing", which not only makes it possible to identify cell populations in a biological sample, but also to quantify the expression of genes specific to each of them. "Until now, RNA sequencing was done on the entire placenta without being able to assign a particular signature to each cell type. This new type of sequencing has the advantage of providing an in-depth analysis of the cellular diversity of an organ, no matter how complex it may be," explains Marie-Claire Vacher, a researcher at Columbia University Medical Center.
First, the researchers distinguished between the different populations of placental cells. Cell groups of exclusively fetal origin included stromal cells, which are involved in the formation of blood cells, endothelial cells, which regulate the permeability of blood vessels, and trophoblastic cells, whose role is to supply the fetus with nutrients and oxygen. On the maternal side, the samples mainly contained cells of the uterine lining, the decidual cells, which change during pregnancy to provide a favorable environment for the implantation of the embryo.
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From cells crucial to inflammation
Most importantly, all the samples contained a large proportion of immune cells (natural killer cells, macrophages, T lymphocytes, B lymphocytes, etc.) produced either by the fetus or by its mother. "All of these cells are involved in the inflammatory processes that occur in all humans as part of infections. Nevertheless, inflammation is a crucial natural process during childbirth. In particular, it plays a role in uterine contractions, dilation of the cervix and the prevention of infections during childbirth," says Yehezkel Ben-Ari, an Inserm researcher specialising in brain maturation processes.
Until now, membranes have been seen as something amorphous in which the fetus bathes. This work is one of the proofs that they actually play an active role during pregnancy.
Prof. Philippe Deruelle, researcher and professor of obstetrics and gynaecology at the Faculty of Medicine of Montpellier-Nîmes.
Once this classification was completed, the researchers turned their attention to the cells' own activity at the time of induction of labour. Surprisingly, the most affected cells were not in the heart of the placenta but in the surrounding membranes, known as "chorioamniotics," which surround the fetus and rupture during labor. "Until now, membranes have been seen as something amorphous in which the fetus bathes. This work is one of many proofs that they actually play an active role during pregnancy," insists Philippe Deruelle, researcher and professor of obstetrics and gynaecology at the Faculty of Medicine of Montpellier-Nîmes.
Moreover, the authors found that certain fetal cells (the "stromal" cells) have a key role in inducing labor. "While the role of maternal cells was suspected, the involvement of fetal cells was less obvious," says Prof. Deruelle. The hypothesis is that they could contribute to the better tolerance of the fetus by the maternal body, in particular through the inhibition of the activity of maternal T lymphocytes, usually responsible for eliminating any foreign body. "Through these complex interactions, the foetus escapes the mother's defence mechanisms and can thus develop without being perceived as a threat," says Prof. Vacher.
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Towards the prediction of preterm births
One of the researchers' most important findings is the identification of potential biomarkers, in the blood of future mothers, of the risk of premature birth. "Despite all the current knowledge and technologies, we are still unable to prevent premature birth, but we know that inflammatory processes play a major role," insists Prof. Deruelle. Such signals are detectable from the beginning of pregnancy, which could be verified by the analysis of blood samples taken during the different trimesters of pregnancy.
These results are very "encouraging", the scientists agree, as it suggests that with the help of a simple blood test, it would be possible to identify certain biomarkers that predict preterm birth. However, the authors remain cautious about this hypothesis, which will have to be confirmed by other studies.