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- Control of human trophoblast function

In order for implantation to occur, endometrium has to be changed into decidua. This process consists in modifying endometrial stromal cells, uterine glands and vessels, as well as the population of uterine immune cells. In humans, unlike other species [1], decidualization is independent of the blastocyst's presence in the uterine cavity and begins in the late secretory phase of the menstrual cycle. It is evoked by progesterone, as well as by regulatory agents able to enhance cyclic AMP (cAMP) levels [2,3]. Decidualization continues in pregnancy, and it is thought to regulate subsequent trophoblast invasion and placenta formation by altering the expression of regulatory factors such as metalloproteinases, cytokines, surface integrins, and major histocompatibility complex molecules. The trophoblast, in turn, releases paracrine signals which modulate decidual stromal cell gene expression [4]. These cells become round and show ultrastructural similarities with myofibroblasts and epithelial cells [5]. Moreover, they release several factors including prolactin, relaxin, renin, insulin-like growth factor binding protein-1 (IGFBP-1) [1,3] and specific extracellular matrix (ECM) proteins such as laminin and fibronectin [6]. In vitro studies have demonstrated that this event is correlated with changes in steroid hormone receptor expression and steroid metabolism, remodeling of the ECM and cytoskeleton, altered expression of enzymes, growth factors and cytokines, and induction of apoptosis modulators and specific transcription factors [7]. Elongation of the spiral arteries occurs through an endometrium-specific angiogenesis, characterized by proliferation of both endothelial and smooth muscle cells, with preservation of the integral structure of the vessel. In the uterine wall, several leukocyte types, such as T lymphocytes, a few B lymphocytes, macrophages, and natural killer (NK) cells, are present. However, after ovulation, a dramatic increase in NK cells is observed. Uterine NK cells (uNK) are phenotypically and functionally different from circulating ones. Indeed, they have not cytolytic activity [8], and express integrins which allow their migration and invasion of the decidualizing endometrium [6]. It has been suggested that the unique environment resulting from the transformation of endometrium to decidua plays a crucial role in uNK cell specificity acquisition [6,9]. Since decidual NK cells decrease in number in the second half of pregnancy and disappear at delivery, it has been hypothesized that their main role is confined to early pregnancy, when they modulate implantation and placentation interacting with both decidual stromal cells and trophoblast [6,9]. Interestingly, it has been shown that uNK cell recruitment is a hormonally-controlled maternal function and is independent of the presence of the implanting embryo [10]. NK cell survival seems to be dependent upon the presence of progesterone, whose action, however, is presumably not direct, but mediated by decidual stromal cells which express hormone receptors [11]. In contrast, it has recently been shown that glucorticoids are able to decrease the number of decidual NK cells [12].

Decidualization is also characterized by a decrease in Th1 and an increase in Th2 lymphocytes, an effect which is evoked by progesterone and cytokines. It has been proposed that Th2 cytokines protect fetus and trophoblasts inhibiting NK cell cytotoxicity and proliferation, shifting NK cell cytokine production toward a Th2 phenotype, as well as suppressing cytotoxic T cells activation [12-14].


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