During early human pregnancy the uterine mucosa transforms into the decidua, into which the fetal placenta implants and where placental trophoblast cells intermingle and communicate with maternal cells. Trophoblast-decidual interactions underlie common diseases of pregnancy, including pre-eclampsia and stillbirth. Here we profile the transcriptomes of about 70,000 single cells from first-trimester placentas with matched maternal blood and decidual cells. The cellular composition of human decidua reveals subsets of perivascular and stromal cells that are located in distinct decidual layers. There are three major subsets of decidual natural killer cells that have distinctive immunomodulatory and chemokine profiles. We develop a repository of ligand-receptor complexes and a statistical tool to predict the cell-type specificity of cell-cell communication via these molecular interactions. Our data identify many regulatory interactions that prevent harmful innate or adaptive immune responses in this environment. Our single-cell atlas of the maternal-fetal interface reveals the cellular organization of the decidua and placenta, and the interactions that are critical for placentation and reproductive success.

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Single-cell reconstruction of the early maternal–fetal interface in humans

Implantation involves an intricate discourse between the embryo and uterus and is a gateway to further embryonic development. Synchronizing embryonic development until the blastocyst stage with the uterine differentiation that takes place to produce the receptive state is crucial to successful implantation, and therefore to pregnancy outcome. Although implantation involves the interplay of numerous signalling molecules, the hierarchical instructions that coordinate the embryo-uterine dialogue are not well understood. This review highlights our knowledge about the molecular development of preimplantation and implantation and the future challenges of the field. A better understanding of periimplantation biology could alleviate female infertility and help to develop novel contraceptives.

Roadmap to embryo implantation: clues from mouse models

The 'seed and soil' hypothesis for metastasis sets forth the concept that a conducive microenvironment, or niche, is required for disseminating tumour cells to engraft distant sites. This Opinion presents emerging data that support this concept and outlines the potential mechanism and temporal sequence by which changes occur in tissues distant from the primary tumour. To enable improvements in the prognosis of advanced malignancy, early interventions that target both the disseminating seed and the metastatic soil are likely to be required.

The metastatic niche: adapting the foreign soil

The epidermal growth factor receptor (EGFR) signaling pathway is one of the most important pathways that regulate growth, survival, proliferation, and differentiation in mammalian cells. Reflecting this importance, it is one of the best-investigated signaling systems, both experimentally and computationally, and several computational models have been developed for dynamic analysis. A map of molecular interactions of the EGFR signaling system is a valuable resource for research in this area. In this paper, we present a comprehensive pathway map of EGFR signaling and other related pathways. The map reveals that the overall architecture of the pathway is a bow-tie (or hourglass) structure with several feedback loops. The map is created using CellDesigner software that enables us to graphically represent interactions using a well-defined and consistent graphical notation, and to store it in Systems Biology Markup Language (SBML).

https://www.embopress.org/doi/pdf/10.1038/msb4100014

A comprehensive pathway map of epidermal growth factor receptor signaling

Successful implantation is the result of reciprocal interactions between the implantation-competent blastocyst and receptive uterus. Although various cellular aspects and molecular pathways of this dialogue have been identified, a comprehensive understanding of the implantation process is still missing. The receptive state of the uterus, which lasts for a limited period, is defined as the time when the uterine environment is conducive to blastocyst acceptance and implantation. A better understanding of the molecular signals that regulate uterine receptivity and implantation competency of the blastocyst is of clinical relevance because unraveling the nature of these signals may lead to strategies to correct implantation failure and improve pregnancy rates. Gene expression studies and genetically engineered mouse models have provided valuable clues to the implantation process with respect to specific growth factors, cytokines, lipid mediators, adhesion molecules, and transcription factors. However, a staggering amount of information from microarray experiments is also being generated at a rapid pace. If properly annotated and explored, this information will expand our knowledge regarding yet-to-be-identified unique, complementary, and/or redundant molecular pathways in implantation. It is hoped that the forthcoming information will generate new ideas and concepts for a process that is essential for maintaining procreation and solving major reproductive health issues in women.

Molecular cues to implantation

A vast array of successive epigenetic modifications ensures the creation of a healthy individual. Crucial epigenetic reprogramming events occur during germ cell development and early embryogenesis in mammals. As highlighted by the large offspring syndrome with in vitro conceived ovine and bovine animals, any disturbance during germ cell development or early embryogenesis has the potential to alter epigenetic reprogramming. Therefore the complete array of human assisted reproductive technology (ART), starting from ovarian hormonal stimulation to embryo uterine transfer, could have a profound impact on the epigenetic state of human in vitro produced individuals. Although some investigators have suggested an increased incidence of epigenetic abnormalities in in vitro conceived children, other researchers have refuted these allegations. To date, multiple reasons can be hypothesized why irrefutable epigenetic alterations as a result of ART have not been demonstrated yet.

/pdf/epigenetics-definition-mechanisms-and-clinical-perspective-3pah9sd8r5.pdf

Epigenetics: definition, mechanisms and clinical perspective.

Physiological and molecular determinants of embryo implantation

During human placentation, extravillous cytotrophoblast cells emerge from chorionic villi contacting the decidua to invade the uterine wall. When isolated from first-trimester placentae, cytotrophoblast cells undergo step-wise differentiation in vitro that recapitulates the phenotypic heterogeneity observed in vivo. We examined a cell line, HTR-8/SVneo, that has been established from human first-trimester cytotrophoblast to determine whether these cells possess some of the unique cytotrophoblast characteristics that have been described previously. Exposure during serum-free culture to hypoxic conditions (2% oxygen concentration) increased HTR-8/SVneo cell proliferation and reduced invasion of a three-dimensional basement membrane (Matrigel). During culture on surfaces coated with individual extracellular matrix proteins, HTR-8/SVneo cells expressed cytokeratin but not the trophoblast-specific major histocompatibility protein, HLA-G. However, HLA-G expression was induced in HTR-8/SVneo cells that contacted Matrigel. Expression of the a5 integrin subunit was relatively unaffected by matrix composition, whereas a1 was up-regulated and a 6w as down-regulated after transferring cells to Matrigel. Hypoxia increased a6 and decreased both a1 and HLA-G expression on Matrigel. HTR-8/SVneo cells retain several important characteristics associated with primary cultures of first-trimester human cytotrophoblast cells, including their altered behavior in response to a changing maternal environment.

https://bioone.org/journals/Biology-of-Reproduction/volume-62/issue-3/biolreprod62.3.739/Extracellular-Matrix-Composition-and-Hypoxia-Regulate-the-Expression-of-HLA/10.1095/biolreprod62.3.739.pdf

D. Randall Armant

Papers

Epigenetics: definition, mechanisms and clinical perspective.

Physiological and molecular determinants of embryo implantation

Extracellular matrix composition and hypoxia regulate the expression of HLA-G and integrins in a human trophoblast cell line.

Toll-like receptor 4: A potential link between “danger signals,” the innate immune system, and preeclampsia?

Blastocysts don’t go it alone. Extrinsic signals fine-tune the intrinsic developmental program of trophoblast cells