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Biology Articles » Anatomy & Physiology » Physiology, Human » Control of human trophoblast function » Blastocyst implantation

Blastocyst implantation
- Control of human trophoblast function

An intimate cross-talk between the embryo and the uterus is needed for blastocyst implantation [4,15]. This process, which consists of an interaction between trophoblast cells and endometrium, can only take place in a restricted period of time, termed "window of receptivity". It is initially dependent upon the presence of estrogen and progesterone, although further morphological and biochemical changes are evoked within the uterine wall by signals from the embryo and invading trophoblast. The "window of receptivity" in humans is presumed to span days 20–24 of the menstrual cycle [1]. Indeed, out of this period the epithelium apical surface is covered by a thick glycocalyx, mainly composed of mucin, and in particular MUC1, a transmembrane glycoprotein characterized by an extended extracellular domain which prevents blastocyst attachment [16]. Blastocyst implantation is also impaired by the large number of desmosomes which exist along lateral epithelial cell surfaces [17]. In some species the "window of receptivity" is characterized by down-regulation of MUC1, but this condition has not been observed in humans. Some researchers have suggested that MUC1 may actually promote human blastocyst attachment to the uterine wall [18], whereas others demonstrated a loss of this mucin at the site of blastocyst interaction [19] thanks to uterine proteases, activated by factors released from the blastocyst itself [16].

Blastocyst attachment to the uterine wall depends upon the interaction between adhesion molecules such as selectins, integrins, and trophinins [17], expressed on both trophoblast cells and uterine epithelium. This interaction is mediated, in most cases, by bridging ligands including, at least in the sheep, osteopontin and galectin-15, which are released in the uterine cavity by endometrial glands [20]. Invasion is favoured by the simultaneous decrease of desmosome density and basal membrane digestion, finally leading to nidation in the decidual stroma [17].

A key role in the control of human blastocyst implantation is exerted by endometrial chemokines and cytokines. Chemokines are thought to be responsible for the promotion of leukocyte migration to the decidua, where they cause a sort of inflammatory state, a process which appears to derive from several sources. First, decidualization is characterized by NK cells interaction with the non-polymorphic HLA class I antigens expressed by invading trophoblasts [21]. Furthermore, signalling agents secreted by seminal vesicles and prostate gland interact with epithelial cells in the cervix and uterus, recruiting and activating macrophages, granulocytes and dendritic cells. They are provided with immune-regulatory and tissue remodelling roles that improve endometrial receptivity to the implanting embryo. Tumor growth factor β (TGF-β) and prostaglandins (PGs) present in seminal fluid contribute to enhance cytokine production and vascular permeability, that appear to be essential for implantation, due to their effects favouring blastocyst attraction and attachment to the endometrium [13]. Moreover chemokines, interacting with G protein-coupled receptors, induce a structural change in integrins which favours adhesion of the blastocyst to the decidualized endometrium [22]. NO favours blastocyst implantation in both animals and humans, modulating PG release, ovarian steroidogenesis, uterine cell proliferation, glandular secretion and blood flow, as well as mediating sex steroid and growth factor actions [15]. Since normal pregnancy is a physiological process, in our opinion it should not be defined as a 'controlled state of inflammation' [23]. However, at an early stage at the implantation site, as well as later systemically, it is regulated by the same cytokines whose derangement can trigger the inflammatory pathway, leading to various types of early and late gestational diseases. Under such profile, the above mentioned 'Th1/Th2' shift hypothesis, that dominated reproductive immunology for many years, should be more simply interpreted as the expression of the modulation of the cytokines that regulate the vascular processes of placentation, rather than a specific mechanism to avoid fetal T-cell rejection.

 


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