Single-cell transcriptomics of the human placenta: inferring the cell communication network of the maternal-fetal interface.

Organismal function is, to a great extent, determined by interactions among their fundamental building blocks, the cells. In this work, we studied the cell-cell interactome of fetal placental trophoblast cells and maternal endometrial stromal cells, using single-cell transcriptomics. The placental interface mediates the interaction between two semiallogenic individuals, the mother and the fetus, and is thus the epitome of cell interactions. To study these, we inferred the cell-cell interactome by assessing the gene expression of receptor-ligand pairs across cell types. We find a highly cell-type-specific expression of G-protein-coupled receptors, implying that ligand-receptor profiles could be a reliable tool for cell type identification. Furthermore, we find that uterine decidual cells represent a cell-cell interaction hub with a large number of potential incoming and outgoing signals. Decidual cells differentiate from their precursors, the endometrial stromal fibroblasts, during uterine preparation for pregnancy. We show that decidualization (even in vitro) enhances the ability to communicate with the fetus, as most of the receptors and ligands up-regulated during decidualization have their counterpart expressed in trophoblast cells. Among the signals transmitted, growth factors and immune signals dominate, and suggest a delicate balance of enhancing and suppressive signals. Finally, this study provides a rich resource of gene expression profiles of term intravillous and extravillous trophoblasts, including the transcriptome of the multinucleated syncytiotrophoblast.

The inflammation paradox in the evolution of mammalian pregnancy: turning a foe into a friend.

A widely discussed physiological puzzle of mammalian pregnancy is the immunological paradox, which asks: why is the semi-allogenic fetus not attacked by the mother's adaptive immune system? Here, we argue that an additional, and perhaps more fundamental paradox is the question: why is embryo implantation so similar to inflammation while inflammation is also the greatest threat to the continuation of pregnancy? Equally puzzling is the question of how this arose during evolution. We call this the inflammation paradox. We argue that acute endometrial inflammation was ancestrally a natural maternal reaction to the attaching blastocyst, a situation still observed in the opossum. Eutherian implantation arose through a transformation of the acute inflammation into a process essential for implantation by causing vascular permeability and matrix reorganization as well as by suppressing the effects deleterious to the fetus. We propose that this model allows us to understand the differences between 'good inflammation' and 'bad inflammation'. Further, it allows us to understand the influence of inflammation on the outcome of pregnancy and maternal health.

Evolution of Gene Expression in the Uterine Cervix related to Steroid Signaling: Conserved features in the regulation of cervical ripening.

The uterine cervix is the boundary structure between the uterus and the vagina and is key for the maintenance of pregnancy and timing of parturition. Here we report on a comparative transcriptomic study of the cervix of four placental mammals, mouse, guinea pig, rabbit and armadillo, and one marsupial, opossum. Our aim is to investigate the evolution of cervical gene expression as related to putative mechanisms for functional progesterone withdrawal. Our findings are: 1) The patterns of gene expression in eutherian (placental) mammals are consistent with the notion that an increase in the E/P4 signaling ratio is critical for cervical ripening. How the increased E/P4 ratio is achieved, however, is variable between species. 2) None of the genes related to steroid signaling, that are modulated in eutherian species, change expression during opossum gestation. 3) A tendency for decreased expression of progesterone receptor co-activators (NCOA1, -2 and -3, and CREBBP) towards term is a shared derived feature of eutherians. This suggests that parturition is associated with broad scale histone de-acetylation. Western-blotting on mouse cervix confirmed large scale histone de-acetylation in labor. This finding may have important implications for the control of premature cervical ripening and prevention of preterm birth in humans.

The fetal-maternal interface of the nine-banded armadillo: endothelial cells of maternal sinus are partially replaced by trophoblast.

BACKGROUND: The evolution of invasive placentation in the stem lineage of eutherian mammals entailed resolution of the incompatibility between a semi-allogenic fetus and the maternal immune system. The haemochorial placenta of nine-banded armadillo (Dasypus novemcinctus) is thought to conceal itself from the maternal immune system to some degree by developing inside a preformed blood sinus, with minimal contact with the uterine connective tissue. In the present study, we elucidate the micro-anatomical relationship between fetal and maternal tissue of the nine-banded armadillo using histochemical and immunohistochemical tools. RESULTS: We conclude that the chorio-allantoic villi are separated from the myometrium by a vascular endothelial layer, as previously proposed. However, we also observe that the trophoblast cells establish direct contact with the endometrial stroma on the luminal side of the endometrium by partially replacing the endothelial lining of the sinus. Further, we demonstrate the presence of leukocytes, perhaps entrapped, in the placental fibrinoids at the interface between the intervillous space and the endometrial arcade. CONCLUSIONS: The trophoblast of the armadillo invades the uterine tissue to a greater extent than was previously believed. We discuss the implications of this finding for the fetal-maternal immune tolerance.

What was the ancestral function of decidual stromal cells? A model for the evolution of eutherian pregnancy.

In human and mouse, decidual stromal cells (DSC) are necessary for the establishment (implantation) and the maintenance of pregnancy by preventing inflammation and the immune rejection of the semi-allograft conceptus. DSC originated along the stem lineage of eutherian mammals, coincidental with the origin of invasive placentation. Surprisingly, in many eutherian lineages decidual cells are lost after the implantation phase of pregnancy, making it unlikely that DSC are necessary for the maintenance of pregnancy in these animals. In order to understand this variation, we review the literature on the fetal-maternal interface in all major eutherian clades Euarchontoglires, Laurasiatheria, Xenarthra and Afrotheria, as well as the literature about the ancestral eutherian species. We conclude that maintaining pregnancy may not be a shared derived function of DSC among all eutherian mammals. Rather, we propose that DSC originated to manage the inflammatory reaction associated with invasive implantation. We envision that this happened in a stem eutherian that had invasive placenta but still a short gestation. We further propose that extended gestation evolved independently in the major eutherian clades explaining why the major lineages of eutherian mammals differ with respect to the mechanisms maintaining pregnancy.