During childbirth, a mysterious dialogue between the cells of the fetus and those of its mother

It is a physiological storm, orchestrated at the border between the placenta and the uterine lining. Labor, the first stage of childbirth during which the cervix dilates and gradually fades, is triggered under the influence of a series of cellular, immune and vascular mechanisms. But this process does not depend only on the mother's body: the fetus itself influences its triggering by releasing chemical signals that stimulate the production of hormones, such as oxytocin, key to uterine contractions. But how does this ballet between a mother and her unborn child take place?

Although the existence of maternal-fetal “communication” had long been suspected, the contributions to this dialogue of each type of cell, whether of maternal or fetal 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 complete atlas of feto-maternal cellular pathways involved in the induction of labor. The results appeared in Science Translational Medicine. Which, their authors hope, will provide a better understanding of what is happening just before a birth.

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To generate such a map, scientists studied 42 placentas collected during childbirth and 159 blood samples taken from women who gave birth at term or prematurely. They sought to identify the types of maternal and fetal cells most affected by the induction of labor. What's 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, we mainly carried out RNA sequencing on an entire placenta sample without being able to attribute a particular signature to each cell type. Cell-to-cell RNA sequencing has the advantage of providing an in-depth analysis of the cellular diversity of an organ, however complex it may be,” explains Claire-Marie Vacher, researcher at Columbia University Medical Center.

First, the researchers distinguished the different populations of placental cells. Among the cell groups of exclusively fetal origin were stromal cells, involved in the formation of blood cells, endothelial cells, which regulate the permeability of blood vessels, and trophoblast cells, whose role is to supply the fetus with nutrients and oxygen. On the maternal side, the samples mainly contained cells from the uterine lining, the decidual cells, which change during pregnancy to provide a favorable environment for the implantation of the embryo.

But above all, all of 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. However, inflammation is a crucial natural process during childbirth. It participates in particular in uterine contractions, in the dilation of the cervix or in preventing infections during childbirth,” underlines Yehezkel Ben-Ari, researcher at Inserm specializing in brain maturation processes.

Once this classification was completed, the researchers became interested in the specific activity of the cells at the time of labor onset. Surprisingly, the most affected cells were not in the heart of the placenta but in the surrounding membranes, called “chorioamniotic”, which surround the fetus and rupture during labor. “Until now, we saw the membranes as something amorphous in which the fetus is immersed. This work is one proof among others that they actually have an active role during pregnancy,” insists Philippe Deruelle, researcher and professor of obstetrics and gynecology at the Faculty of Medicine of Montpellier-Nîmes.

Furthermore, the authors discovered that certain fetal cells (“stromal” cells) have a key role in triggering labor. “If we suspected the role of maternal cells, the involvement of fetal cells was less obvious,” comments Professor Deruelle. The hypothesis is that they could contribute to better tolerance of the fetus by the maternal body, in particular via inhibition of the activity of maternal T lymphocytes, usually responsible for eliminating any foreign body. “Through these complex interactions, the fetus escapes the mother's defense mechanisms and can thus develop without being perceived as a threat,” believes Professor Vacher.

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One of the most important findings of researchers remains the identification of potential biomarkers, in the blood of future mothers, of the risk of premature birth. “Despite all current knowledge and technologies, we are still unable to prevent premature birth, but we know that inflammatory processes strongly contribute to it,” insists Professor Deruelle. Such signals would be detectable from the start of pregnancy, which could be verified thanks to the analysis of blood samples taken during the different trimesters of pregnancy.

These results are very “encouraging”, the scientists agree, because it suggests that with the help of a simple blood test, it would be possible to identify certain biomarkers predictive of premature births. However, the authors remain cautious about this hypothesis, which will need to be confirmed by other work.