What is the name of the vascular structure that nourishes and connects the developing embryo to the uterine wall?

Ectopic Decidua

In pregnant women, ectopic decidua is a common finding within the submesothelial stroma of the pelvic peritoneum and omentum and, less commonly, within the superficial cortex of abdominopelvic lymph nodes.181,259–264 Ectopic decidua is typically an incidental microscopic finding, but florid peritoneal lesions may be visible at the time of cesarean section or postpartum tubal ligation as multiple, gray-white focally hemorrhagic nodules or plaques studding the peritoneal surfaces and simulating a malignant tumor. Several cases have been associated with massive, occasionally fatal, hemoperitoneum during the third trimester, labor, or the puerperium. One florid case of peritoneal decidual reaction was associated with obstruction of labor.264 Four cases of appendiceal deciduosis mimicking acute appendicitis during pregnancy have also been described.265 Ectopic decidua usually involutes by the sixth postpartum week.

On microscopic examination, the ectopic decidual cells are disposed individually or arranged in nodules or plaques and typically resemble eutopic decidua (Figs. 15.56, 15.57, and 15.58). Smooth muscle cells, probably derived from submesothelial myofibroblasts, may be admixed. The decidual foci are often vascular (seeFig. 15.56) and may contain a sprinkling of lymphocytes. Focal hemorrhagic necrosis and varying degrees of nuclear pleomorphism and hyperchromasia of the decidual cells may rarely suggest a malignant tumor, and misinterpretation as metastatic squamous cell carcinoma is a potential diagnostic pitfall.259,262 The bland appearance of most of the decidual cells and an absence of mitotic figures point to the correct diagnosis. It should be noted, however, that occasionally ectopic decidua and metastatic squamous cell carcinoma can involve the same lymph node.260 Ectopic decidual cells, like their eutopic counterparts, occasionally contain an eccentric nucleus and cytoplasmic vacuoles with basophilic mucin (seeFig. 15.58). In such cases, some of the cells can resemble the signet ring cells of a carcinoma but, in contrast to the latter, contain only acidic mucin within the vacuoles and show negative staining for epithelial markers such as cytokeratin.

Introduction

Decidualization denotes the transformation of the endometrial stroma into the decidual matrix that supports embryo implantation and subsequent placenta formation. This process is foremost characterized by the differentiation of endometrial stromal cells (EnSCs) into secretory decidual cells (Gellersen and Brosens, 2014). Decidualization only occurs in species where the trophoblast breaches the luminal endometrial epithelium and invades maternal tissues. The depth of decidual transformation is determined by the degree of placental trophoblast invasion (Ramsey et al., 1976). In most mammals, decidualization is initiated upon embryo implantation. However, in a handful of species, including humans, Old World monkeys, some bats, elephant shrew, and spiny mouse, decidualization is “spontaneous,” meaning that it is initiated independently of an implanting embryo during the midluteal phase of each cycle (Emera et al., 2012). Once triggered, the decidual phenotype is strictly dependent on sustained progesterone signaling. In the absence of pregnancy, falling ovarian progesterone production triggers a cascade of inflammatory events in the decidualizing endometrium, which upon recruitment and activation of leucocytes becomes irrevocable and leads to partial tissue destruction, bleeding and menstrual shedding. Hence, spontaneous decidualization is inextricably linked to cyclic menstruation; and the term “decidua,” derived from the Latin verb “decidere” (meaning to fall off, to detach, or to die), aptly captures the nature of the process.

Although decidual transformation of EnSCs starts during the midluteal phase of the cycle, characteristic morphological changes are apparent only at the onset of the late-luteal phase, that is approximately 9–10 days after the postovulatory rise in circulating progesterone levels (Fig. 1). Decidualizing cells lose their fibroblastic appearance and become enlarged. They are further characterized by rounding of the nucleus, enlargement of the rough endoplasmic reticulum and Golgi apparatus, and accumulation of glycogen and lipid droplets (Gellersen and Brosens, 2014). Because of this expansion of the cellular secretory machinery, many genes that are constitutively expressed in epithelial cells are induced in EnSCs upon decidualization. The lag-period between ovulation and the onset of decidual process reflects the fact that transcriptional activation of decidual genes is strictly dependent on a sharp rise in intracellular production of the second messenger cyclic adenosine monophosphate (cyclic AMP) during the luteal phase. Cyclic AMP activates protein kinase A and induces the expression of decidua-specific transcription factors, such as the Forkhead box protein O1 (FOXO1), HOXA10 (Homeobox A10) and HOXA11, CCAAT-enhancer-binding proteins (C/EBPs). Once the decidual process is initiated, the liganded progesterone receptor (PGR) physically binds these core decidua-specific transcription factors, thus maintaining and amplifying the expression of differentiation genes, including PRL (coding prolactin) and IGFBP1 (insulin-like growth factor-binding protein 1) (Gellersen and Brosens, 2014).

Typically, decidual transformation starts with EnSCs around the spiral arteries and underlying the luminal epithelium. Short- and long-range cytokines and morphogens then control the spatiotemporally progression of the decidual process, which in pregnancy encompasses the entire endometrium. It is important to note that decidualization of the stroma occurs in concert with profound changes in glandular gene expression and influx of immune cells, especially uterine natural killer (uNK) cells and, to a lesser extent, macrophages. For an in-depth description of the molecular drivers of decidualization, we refer the reader to a recent review (Gellersen and Brosens, 2014). Here we focus on the emerging functions of the decidual process that enables the endometrium to transit from a cycling to a gestational tissue.

The presence of an embryo leads to decidualization of the endometrium

During the middle to late secretory phase of the normal endometrial cycle, the endometrium becomes more vascularized and thicker, and the endometrial glands become tortuous and engorged with secretions (see pp.1125–1126). These changes, driven by progesterone from the corpus luteum, peak at ~7 days after ovulation. Additionally, beginning 9 to 10 days after ovulation, a process known aspredecidualization (see pp.1125–1126) begins near the spiral arteries. During predecidualization, stromal cells transform into rounded decidual cells, and these cells spread across the superficial layer of the endometrium to make it more compact (zona compacta) and separating it from the deeper, more spongy layer (zona spongiosa; seeFig. 55-11). If conception fails to occur, the secretory activity of the endometrial glands decreases, followed by regression of the glands 8 to 9 days after ovulation, which is ultimately followed by menstruation.

When pregnancy occurs, the predecidual changes in the endometrium are sustained and extended, which completes the process ofdecidualization. Thedecidua is the specialized endometrium of pregnancy. Its original name wasmembrana decidua, a term referring to the membranes of the endometrium that are shed following pregnancy, like the leaves of a deciduous tree. Because the degree of decidualization is considerably greater in conception cycles than in nonconception cycles, it is likely that the blastocyst itself promotes decidualization. Indeed, either the presence of the embryo or a traumatic stimulus that mimics the embryo's invasion of the endometrium induces changes in the endometrium.

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Onset of Decidualization

One of the earliest signs that the blastocyst has transmitted an embryonic signal to the endometrium is a marked increase in the permeability of endometrial capillaries. One can detect this permeability increase by injecting laboratory rats intravenously with a dye, such as Evans blue, which binds to albumin. Accumulation of blue dye in the area of the blastocyst is an index of increased capillary permeability to albumin. Increased endometrial capillary permeability precedes the decidual response and may be triggered by vasoactive substances released by the blastocyst just prior to implantation. Because inhibitors of histidine decarboxylase (which converts histidine to histamine) interrupt implantation, histamine is one candidate for the vasoactive substance.

The area underneath the implanting embryo becomes thedecidua basalis (Fig. 56-3). Other portions of the decidua that become prominent later in pregnancy are thedecidua capsularis, which overlies the embryo, and thedecidua parietalis, which covers the remainder of the uterine surface. The upper zona compacta layer and the middle zona spongiosa layer of the nonpregnant endometrium are still recognizable in the decidualized endome­trium of pregnancy. The glandular epithelium within the zona spongiosa continues its secretory activity during the first trimester. Some of the glands take on a hypersecretory appearance in what has been referred to as theArias-Stella phenomenon of early pregnancy—named after the pathologist Javier Arias-Stella. Although the decidualized endometrium is most prominent during the first trimester, prior to the establishment of the definitive placenta, elements of decidualization persist throughout gestation.

Abstract

The decidua, a specialized tissue layer formed from the endometrium, provides structural and vascular support to the fetus and placenta. The decidua also plays an important immunoregulatory role as it controls the local trafficking and behavior of maternal immune cells in several key ways that contribute to pregnancy success. Here, we discuss how the decidua, and in particular its dominant parenchymal component, the decidual stromal cell, modulates the immune environment around the developing conceptus. This modulation occurs in a dynamic fashion, from the time of embryo implantation all the way through parturition, employing both inflammatory and antiinflammatory pathways.

Decidua

Thedecidua is the endometrium of the uterus in a pregnant woman. It is the functional layer of the endometrium that separates from the remainder of the uterus afterparturition (childbirth). Thethree regions of the decidua are named according to their relation to the implantation site (seeFig. 7.1):

Thedecidua basalis is the part of the decidua deep to the conceptus which forms the maternal part of the placenta.

Thedecidua capsularis is the superficial part of the decidua overlying the conceptus.

Thedecidua parietalis represents the remaining parts of the decidua.

In response to increasing progesterone levels in maternal blood, the connective tissue cells of the decidua enlarge to formdecidual cells. These cells enlarge as glycogen and lipid accumulate in theircytoplasm.

The cellular and vascular changes occurring in the endometrium as the blastocyst implants constitute thedecidual reaction. Many decidual cells degenerate near thechorionic sac in the region of thesyncytiotrophoblast (outer layer of trophoblast), and together with maternal blood and uterine secretions, they provide a rich source of nutrition for the embryo/fetus. It has also been suggested that these cells protect the maternal tissue against uncontrolled invasion by the syncytiotrophoblast, and they may be involved in hormone production. Decidual regions, clearly recognizable during ultrasonography, are important in diagnosing early pregnancy (seeChapter 3,Fig. 3.7).

Gross Relationships of Chorionic and Decidual Tissues

Within days after implantation of the embryo, the stromal cells of the endometrium undergo a striking transformation called the decidual* reaction. After the stromal cells swell as the result of the accumulation of glycogen and lipid in their cytoplasm, they are known as decidual cells (Fig. 7.6). The decidual reaction spreads throughout stromal cells in the superficial layers of the endometrium. The maternal decidua are given topographic names based on where they are located in relation to the embryo.

The decidual tissue that overlies the embryo and its chorionic vesicle is the decidua capsularis, whereas the decidua that lies between the chorionic vesicle and the uterine wall is the decidua basalis (Fig. 7.7). With continued growth of the embryo, the decidua basalis becomes incorporated into the maternal component of the definitive placenta. The remaining decidua, which consists of the decidualized endometrial tissue on the sides of the uterus not occupied by the embryo, is the decidua parietalis.

In human embryology, the chorion is defined as the layer consisting of the trophoblast and the underlying extraembryonic mesoderm (see Fig. 7.1). The chorion forms a complete covering (chorionic vesicle) that surrounds the embryo, amnion, yolk sac, and body stalk. During the early period after implantation, primary and secondary villi project almost uniformly from the entire outer surface of the chorionic vesicle. The formation of tertiary villi is asymmetric, however, and the invasion of the cytotrophoblastic core of the primary villi by mesenchyme and embryonic blood vessels occurs preferentially in the primary villi located nearest the decidua basalis. As these villi continue to grow and branch, the villi located on the opposite side (the abembryonic pole) of the chorionic vesicle fail to keep up and eventually atrophy as the growing embryo complex bulges into the uterine cavity (see Fig. 7.7). The region that contains the flourishing chorionic villi and that ultimately becomes the placenta is the chorion frondosum. The remainder of the chorion, which ultimately becomes smooth, is the chorion laeve (Fig. 7.8).

One suggested mechanism for the formation of the chorion laeve is based on oxidative stress. The normal early embryonic environment is roughly equivalent to 3% oxygen, as opposed to the normal 21% atmospheric oxygen level. The uterine spiral arteries in the region of the future chorion laeve are not as tightly sealed by cytotrophoblastic plugs as those under the area of the future placenta. This situation leads to a significant local increase in oxygen concentration, thus causing degeneration of the syncytiotrophoblast that covers the villi and the regression of the capillary circulation within them as a result of oxidative stress.

The overall growth of the chorionic vesicle (Fig. 7.9), with its bulging into the uterine lumen, pushes the decidua capsularis progressively farther from the endometrial blood vessels. By the end of the first trimester, the decidua capsularis itself undergoes pronounced atrophy. Within the next month, portions of the atrophic decidua capsularis begin to disappear and leave the chorion laeve in direct contact with the decidua parietalis on the opposite side of the uterus (see Fig. 7.7). By midpregnancy, the decidua capsularis has fused with the tissues of the decidua parietalis, thereby effectively obliterating the original uterine cavity. While the chorion laeve and decidua capsularis are undergoing progressive atrophy, the placenta takes shape in its definitive form and acts as the main site of exchange between the mother and embryo.

Deciduosis (Ectopic Decidua)

Ectopic decidua of the ovary is a common finding during pregnancy and is often present on the ovarian surface and within the ovarian cortex. It is a physiologic response of coelomic mesenchyme to increased levels of progesterone during pregnancy or exogenous administration. Ovarian ectopic decidua is an incidental finding in the majority of cases.

Macroscopically, ectopic decidua is seen as a tan or red spot on the ovarian surface. At microscopic examination, the cells of ectopic decidua are similar to the cells of decidualized endometrium. The cells form sheets of large polygonal cells with sharp cell borders; round, centrally placed nuclei; vesicular chromatin; small nucleoli; and abundant pale eosinophilic cytoplasm. Occasionally, intercellular edema is conspicuous. Involvement of paraovarian adhesions and peritoneal surfaces is also common (Fig. 22.28).

In extraovarian sites, deciduosis may be mistaken for neoplasms, including mesothelioma (see Chapter 23); and when extensive, they may be mistaken for carcinomatosis.48 This diagnostic error is unlikely in the ovary, although decidualized endometrium cysts may occasionally be misdiagnosed as neoplasms on ultrasound. The principal differential in the ovary is smooth muscle metaplasia (Fig. 22.29).

Decidua

D Preparation of Mouse Embryo

The embryos are dissected as described in Hogan et al. (1986) from timed pregnant mice at 7.5–7.75 days post coitum. Nodal flow is a transient phenomenon during development and can only be observed in embryos from midneural plate stage to 3–4 somite stage (Okada et al., 1999). Thus, the time window for the observation is very narrow and varies by the mouse strain or even by the mouse supplier.

2 Collection of the Embryos

Under a stereomicroscope, the decidual tissue is then torn into two halves in PB1 medium by pulling apart the cleft at the mesometrial pole with fine forceps (Fig. 3A). One half of the deciduum retains the embryo. The remaining half of the deciduum can be removed similarly by peeling it off along the long axis of the embryo (Fig. 3B). Finally the embryo is detached from the remaining strip of deciduum with the tip of fine forceps. Alternatively, you can cut the whole deciduum into two halves along the long axis of the surface of the embryo with fine scissors and shell out the exposed embryo with the tips of fine forceps.

Fig. 3. Dissection and preparation of the mouse embryo. See main text for detail.

Decidua

The decidua is a transient layer that is localized between the fetal membranes and the myometrium and may play a role in the cross-talk between maternal and fetal compartments. It is formed during the secretory phase of the menstrual cycle as a result of elevated ovarian hormones such as estrogen and progesterone. The decidua is composed of glands, immune cells, blood and lymph vessels, and decidual stromal cells (DSCs) and fetal extravillous trophoblast (Mori et al., 2016). The interaction of the maternal leukocyte populations in the decidua with fetal trophoblasts is crucial at the time of placentation and for the success of pregnancy. Therefore, any disturbance in the decidualization process and/or maternal-fetal crosstalk could lead to pregnancy complications such as implantation failure and pregnancy loss (Sharma, S. et al., 2016).

There are three major process in which maternal-fetal cross-talk is essential for the maintenance of pregnancy: a) the establishment of immune tolerance, b) regulation of the trophoblast invasion, and c) remodeling of the spiral arteries (Romero et al., 2014). Defects in trophoblast invasion are associated with severe pregnancy complications affecting both mother and fetus. Cytokines and growth factors are key molecules involved in the regulation of trophoblast invasion and act either to stimulate such as IL-1β, Il-6, IL-11, IL-8, RANTES, and IP-10 or inhibit; IL-10, IL-12 and vascular endothelial growth factor (VEGF) (Sharma et al., 2016).

Given their anatomical position, decidual cells are likely to be the first cells of the feto-maternal interface to be in contact and respond to pathogens and establish the immunotolerance mechanisms towards fetal antigens (Anders et al., 2017). There are several critical windows in which the maternal immune system may be challenged with fetal alloantigens at the decidua: i) during implantation, ii) when extravillous trophoblast invade and remodel the maternal spiral arteries, iii) when the syncytiotrophoblast turnover sheds microvesicles, nanoparticles, microparticles and exosomes into maternal circulation. The female immune system undergoes constant transformation and adaptation beginning with each menstrual cycle and continuing through gestation with fertilization and implantation. Changes in the immune cell populations, secretory profiles and the immune effects of pregnancy-associated hormones in the decidua are some of the maternal adaptations allowing for immunotolerance (Hyde and Schust, 2016).

The establishment of the fetal–maternal unit is fundamental for the establishment and maintenance of pregnancy. This maternal-fetal interface serves two principal functions: (1) to act as an interface between the mother and fetus and allow nutrient and oxygen transfer and waste products removal, a function mainly orchestrated by the placenta; and (2) to protect the fetus from the extrauterine environment until it is fully developed, a function served by the fetal membranes and decidua. Although the structure and some functions of the fetal-maternal unit may vary between species, the endocrine and transport functions in the unit remain consistent. Abnormal establishment of the fetal-maternal unit may be involved in the pathogenesis of impaired implantation, recurrent miscarriages, intrauterine growth restriction and preeclampsia.