The complexity of the events of embryo implantation and placentation is exemplified by the number and range of cytokines with demonstrated roles in these processes. Disturbance of the normal expression or action of these cytokines results in complete or partial failure of implantation and abnormal placental formation in mice or humans. Of known importance are members of the gp130 family such as interleukin-11 (IL-11) and leukaemia inhibitory factor (LIF), the transforming growth factor β (TGFβ) superfamily including the activins, the colony-stimulating factors (CSF), the IL-1 system and IL-15 system. New data are also emerging for roles for a number of chemokines (chemoattractive cytokines) both in recruiting specific cohorts of leukocytes to implantation sites and in trophoblast differentiation and trafficking. This review focuses on those cytokines and chemokines whose expression pattern in the human endometrium is consistent with a potential role in implantation and placentation and for which some relevant actions are known. It examines what is known of their regulation and action along with alterations in clinically relevant situations.

Exosomes are nanoparticles (∼100 nm diameter) released from cells, which can transfer small RNAs and mRNA via the extracellular environment to cells at distant sites. We hypothesised that exosomes or the slightly larger microvesicles (100–300 nm) are released from the endometrial epithelium into the uterine cavity, and that these contain specific micro (mi)RNA that could be transferred to either the trophectodermal cells of the blastocyst or to endometrial epithelial cells, to promote implantation. The aim of this study was to specifically identify and characterise exosomes/microvesicles (mv) released from endometrial epithelial cells and to determine whether exosomes/mv are present in uterine fluid. Immunostaining demonstrated that the tetraspanins, CD9 and CD63 used as cell surface markers of exosomes are present on the apical surfaces of endometrial epithelial cells in tissue sections taken across the menstrual cycle: CD63 showed cyclical regulation. Exosome/mv pellets were prepared from culture medium of endometrial epithelial cell (ECC1 cells) and from uterine fluid and its associated mucus by sequential ultracentifugation. Exosomes/mv were positively identified in all preparations by FACS and immunofluorescence staining following exosome binding to beads. Size particle analysis confirmed the predominance of particles of 50–150 nm in each of these fluids. MiRNA analysis of the ECC1 cells and their exosomes/mv demonstrated sorting of miRNA into exosomes/mv: 13 of the 227 miRNA were specific to exosomes/mv, while a further 5 were not present in these. The most abundant miRNA in exosomes/mv were hsa-miR-200c, hsa-miR-17 and hsa-miR-106a. Bioinformatic analysis showed that the exosome/mv-specific miRNAs have potential targets in biological pathways highly relevant for embryo implantation. Thus exosomes/mv containing specific miRNA are present in the microenvironment in which embryo implantation occurs and may contribute to the endometrial-embryo cross talk essential for this process.

Transforming growth factor β (TGFβ) superfamily members are closely associated with tissue remodelling events and reproductive processes. This review summarises the current state of knowledge regarding the expression and actions of TGFβ superfamily members in the uterus, during the menstrual cycle and establishment of pregnancy. TGFβs and activin β subunits are abundantly expressed in the endometrium, where roles in preparation events for implantation have been delineated, particularly in promoting decidualisation of endometrial stroma. These growth factors are also expressed by epithelial glands and secreted into uterine fluid, where interactions with preimplantation embryos are anticipated. Knockout models and embryo culture experiments implicate activins, TGFβs, nodal and bone morphogenetic proteins (BMPs) in promoting pre- and post-implantation embryo development. TGFβ superfamily members may therefore be important in the maternal support of embryo development. Following implantation, invasion of the decidua by fetal trophoblasts is tightly modulated. Activin promotes, whilst TGFβ and macrophage inhibitory cytokine-1 (MIC-1) inhibit, trophoblast migration in vitro, suggesting the relative balance of TGFβ superfamily members participate in modulating the extent of decidual invasion. Activins and TGFβs have similar opposing actions in regulating placental hormone production. Inhibins and activins are produced by the placenta throughout pregnancy, and have explored as a potential markers in maternal serum for pregnancy and placental pathologies, including miscarriage, Down’s syndrome and pre-eclampsia. Finally, additional roles in immunomodulation at the materno-fetal interface, and in endometrial inflammatory events associated with menstruation and repair, are discussed.

Implantation failure and inadequate placental development are important contributors to infertility, recurrent miscarriage, and other pregnancy-related problems in women. Better understanding of these processes is hampered by the difficulty in obtaining human tissue from which primary cells can be prepared and by the very limited access worldwide to human blastocysts for experimentation. Therefore, the use of appropriate cell lines, particularly for functional studies of implantation and placentation, is imperative. While a number of cell lines for both endometrium and trophoblast have been developed and are widely used, it is difficult for researchers to decide which of these are most appropriate for studies of particular functions. This brief review summarizes the known phenotypes of the most widely used cell lines and indicates which might be the most appropriate for individual studies.