Intricate and precise communication between the blastocyst and the uterus orchestrates embryo implantation. However, many questions remain unanswered regarding the molecular complexities of implantation. On-time implantation requires a receptive uterus and a mature blastocyst with trophoblast cells capable of adhering to and invading the endometrium. Defects in uterine receptivity or embryo/uterine signaling can cause implantation failure or early pregnancy loss, whereas deficient trophoblast differentiation can generate placental abnormalities that produce adverse pregnancy outcomes. This review will discuss several examples of signaling pathways that regulate trophoblast and uterine development during this period. Leukemia inhibitory factor is involved in uterine priming for implantation. The epidermal growth factor signaling system contributes to trophoblast-uterine communication, as well as trophoblast adhesion and invasion. Indian hedgehog signaling synchronizes tissue compartments within the uterus, and WNT signaling mediates numerous interactions within the implantation site and developing placenta. The autocrine, paracrine and juxtacrine interactions mediated by these signaling pathways contribute significantly to the establishment of pregnancy, although there are many other known and yet to be discovered factors that synchronize the maternal and embryonic developmental programs.
Although not belonging to the class of professional phagocytes, in many speciestrophoblast cells exhibit intense phagocytic activity. The complete range of physiological functionsof trophoblast phagocytosis has not yet been fully characterized. Close association betweenthe trophoblast and nutrition was determined many years ago. Hubrecht (1889) when proposingfor the first time the name trophoblast to the external layer of the blastocyst, directly establishedthe nutritive significance of this embryonic layer. Indeed, histotrophic phagocytosis, i.e. theinternalization of maternal cells and secreted materials, is considered an important function of thetrophoblast before the completion of the placenta. Recently, however, unexpected characteristicsof the trophoblast have significantly enhanced our understanding of this process. Roles inacquisition of space for embryo development, in tissue remodeling during implantation andplacentation and in defense mechanisms are highlighting how this cellular activity may berelevant for the maternal-fetal relationship beyond its nutritional function.
Precise and local control of the innate immune system within the placenta is an essential component for achieving a normal and healthy pregnancy. One of the most abundant immune cells of the placenta is a subpopulation of natural killer (NK) cells that profusely populates the uterine decidua during early pregnancy. Uterine NK (uNK) cells and trophoblast cells of the placenta communicate both directly and indirectly to contribute to the critical process of spiral artery remodeling. Here, we discuss recent findings that expand our knowledge of uNK cell-trophoblast cell crosstalk and the important role it plays in the maternal vascular adaptation to pregnancy.
The present review deals with the trophoblast structure during the free intrauterine life of the pig blastocyst. The term trophoblast is used here to describe the association of the first extraembryonic cell layers, the trophectoderm and the primitive endoderm that are polarized epithelia, a fact established by ultrastructural and immunocytochemical data. The aim of this synthesis is to gather the relative works dispersed in the litterature and to explain the implication of the planar polarity of these cell layers on their developmental fate and roles. These epithelia are intricately dependent on each other for the maintenance of their differentiated state and continuity. The modalities of their spectacular expansion can be explained in part by biomechanical concepts.
Implantation of the embryo into the uterus triggers the initiation of hemochorial placentation. The hemochorial placenta facilitates the acquisition of maternal resources required for embryo/fetal growth. Uterine spiral arteries form the nutrient supply line for the placenta and fetus. This vascular conduit undergoes gestation stage-specific remodeling directed by maternal natural killer cells and embryo-derived invasive trophoblast lineages. The placentation site, including remodeling of the uterine spiral arteries, is shaped by environmental challenges. In this review, we discuss the cellular participants controlling pregnancy-dependent uterine spiral artery remodeling and mechanisms responsible for their development and function.
Trophoblastic cell fusion is one essential step of the human trophoblast differentiationpathway and is a multifactorial and dynamic process finely regulated and still poorly known.Disturbances of syncytiotrophoblast formation are observed in numerous pathological clinicalconditions such as preeclampsia, intrauterine growth retardation and trisomy 21. In this review,we summarize current knowledge of the different membrane proteins directly involved introphoblastic cell fusion, which we identified by using the physiological model of primary cultureof villous trophoblastic cells. Connexin 43 and gap junctional intercellular communication pointto the role of molecular exchanges through connexin channels preceding membrane fusion. Zonaoccludens-1, which can interact with connexin 43, is also directly involved in trophoblast fusion.The recently identified fusogenic membrane retroviral envelop glycoproteins syncytin 1 (encodedby the HERV-W gene) and syncytin 2 (encoded by the FRD gene) and their receptors are majorfactors involved in human placental development . We describe the increasing number of factorspromoting or inhibiting trophoblast fusion and differentiation and emphasize the role of humanchorionic gonadotropin (hCG) and its receptor. Indeed, in trisomy 21 the dynamic process leadingto membrane fusion is impaired due to an abnormal hCG signaling. This abnormal trophoblastfusion and differentiation in trisomy 21-affected placenta is reversible in vitro. Trisomy 21trophoblastic cell culture may therefore be useful to identify the possible large number ofprerequisite factors involved in trophoblast fusion, the limiting step of trophoblast differentiation.
The common gestational pathologies are placental and developmental in origin.However, much remains to be learned about the key events of morphogenesis and growth in theplacenta. Metabolic settings established early in both the fetus and placenta define their capacityto respond to later challenges, as well as the quality of the response. Placental growth isexponential in the first trimester and involves coordinated events in trophoblast and mesenchyme,with early cell segregation events having a strong influence on growth potential. One ofthese is the differentiation of progenitor cytotrophoblasts into villous intermediate cells programmedto fuse with the syncytium, or, alternatively, into extravillous migratory cells thattransform the maternal vascular supply. In the latter case, contact with decidual extracellularmatrix stimulates differentiation, and therefore this decision is influenced by the number ofcontact sites at the placental periphery, which in turn is a function of branching in the villous tree.The villous trophoblast bilayer is the primary barrier between maternal and fetal tissues. Thematernal-facing layer is syncytial and post-mitotic: this limits traffic of pathogens to the fetus andchimaerism arising by shedding of (non-proliferative) syncytial elements into maternal circulation.Conventional cell culture models fail to replicate this critical vectorial relationship. Tissueexplants can overcome the problem to some extent, and have been used to show that turnoverof trophoblast in the villous environment is regulated by signals from both fetal and maternaltissues. Maternally delivered insulin-like growth factors stimulate growth and might be therapeuticallyuseful when endogenous growth pathways falter.
DNA methylation functions as cellular memory beyond generations of cells and is involved in many biological processes. Because of its relatively stable nature compared with the transcriptome, the DNA methylation profile of cells can also be used to evaluate developmental similarity and cellular phenotypes. Recent insights into 5-hydroxymethylcytosine have started to reshape our view of the epigenetic regulation of mammalian development. Both global DNA methylation and hydroxymethylation levels change dynamically during preimplantation embryogenesis. It is known that DNA methylation plays an essential role in embryonic cell fate restriction, whereas its role in trophoblast development requires further research. Two distinct blastocyst-derived stem cell lines, embryonic stem (ES) cells and trophoblast stem (TS) cells, are used to study the epigenetic mechanisms underlying cell lineage maintenance and the regulation of cell differentiation. Such studies will allow us to understand the details of the epigenetic landscape of trophoblast development, which should offer valuable information for managing pregnancy-related diseases in humans.
Since the derivation of human embryonic stem cells, and the subsequent generation of induced pluripotent stem cells, there has been much excitement about the ability to model and evaluate human organ development in vitro. The finding that these cells, when treated with BMP4, are able to generate the extraembryonic cell type, trophoblast, which is the predominant functional epithelium in the placenta, has not been widely accepted. This review evaluates this model, providing comparison to early known events during placentation in both human and mouse and addresses specific challenges. Keeping in mind the ultimate goal of understanding human placental development and pregnancy disorders, our aim here is two-fold:to distinguish gaps in our knowledge arising from mis- or over-interpretation of data, and to recognize the limitations of both mouse and human models, but to work within those limitations towards the ultimate goal.
Preeclampsia is a severe pregnancy complication in part due to insufficient implantation. This study aimed at elucidating the mechanism of action of dipeptidyl peptidase IV (DPPIV) in preeclampsia. Small activating RNAs (saRNA) were used to upregulate DPPIV expression in human trophoblast JAR cells. The DPPIV expression level was analyzed by real-time quantitative PCR and western blot and its activity was measured by luminescent protease assay. MMP-9 activity was analyzed by zymography and cell invasion by matrigel invasion assay. DPPIV expression level and activity was significantly increased by saRNA in JAR cells. DDPIV specific inhibitor diprotin A inhibited its activity at both basal and activated levels. DPPIV did not regulate MMP-9 expression but did repress MMP-9 activity. The invading ability of JAR cells was reduced by saRNA but increased by diprotin A. DPPIV might be responsible for the shallow implantation of the placenta due to its inhibition of the invading ability of extravillous trophoblasts, causing preeclampsia at later stage of pregnancy.