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The placenta is the first organ created by a newly implanted embryo (GD5.0), although its form varies considerably until the definitive placenta (DP) becomes active (GD12.5). The placenta acts as an interface for exchanging gases and organic molecules between the embryonic and maternal circulations, a hormone source that regulates maternal processes need to sustain pregnancy, and a protective environment for embryonic survival and growth. The decidua also serves as a barrier to reduce immunogenicity of embryonic proteins. The structure, function, and molecular signature of the placenta is revised greatly over time in response to the growing embryo's evolving metabolic demands [4, 16, 17, 44, 45].

The YS is the first functional placenta (Figure 5.3). It forms shortly after implantation and acts until about GD10.5 as the sole means of gas exchange (by diffusion) and macromolecular transfer (by trophoblast phagocytosis, a process termed “histiotrophic nutrition”) [45, 46]. The YS also serves as the main hematopoietic organ in embryos from about GD8 to GD11 by virtue of the “blood islands” that form at multiple sites near YS blood vessels [8].

At about GD12.5, the DP becomes the main functionally mature placenta (Figure 5.4). This transition is required to provide enhanced blood flow for increased nutrient exchange (a process termed “hemotrophic nutrition”). The mouse DP is a discoid, trihemochorial, chorioallantoic‐derived interface. A discoid arrangement indicates that the region for gas and nutrient exchange is a discrete mass rather than spread over the entire placental surface, while the trihemochorial organization means that maternal blood runs in blood‐filled labyrinth trophoblast‐lined channels lacking an endothelial lining (termed “sinusoids”) and embryonic blood flows through a dense labyrinth comprised of embryonic endothelial‐lined embryonic capillaries that are surrounded by one to three embryonic trophoblast layers. The chorioallantoic derivation means that the DP originates from both chorionic plate (extra‐embryonic ectoderm) and allantois (extra‐embryonic mesoderm) [45].

The late‐gestation placenta consists of multiple distinct regions, which are discerned based on their location and distinct cell composition (Figures 5.3–5.5). The amnion is a thin, translucent membrane that envelops the embryo. The next membrane further from the embryo is the YS, which now is highly vascular and covered on its outer surface by an acellular matrix termed Reichert's membrane (RM). The allantois is a thin, irregular column extending from the ventral abdomen to the flat bottom surface of the DP disc; this allantoic bridge eventually forms the umbilical cord. The DP disc is partitioned into distinct areas. The chorion is the red central plaque that serves as the site where the allantois fuses. The labyrinth is a dense spongy mesh covering the chorion. The labyrinth consists of embryonic capillaries and maternal sinusoids arranged in tortuous, parallel channels to maximize countercurrent blood flow for the most efficient nutrient transfer [47]. The labyrinth represents about 50% of the DP mass once the organ reaches its maximal size at about GD12.5. The junctional zone (JZ) is the middle layer located between the labyrinth and uterine wall. Blood vessels in the JZ contain only maternal blood. A trophoblast giant cell layer sits atop the JZ as a discontinuous, thin border that abuts the decidua basalis. As gestation progresses, the outer layers contain growing numbers of periodic acid Schiff (PAS)‐positive glycogen cells [48]. Specific trophoblast populations in the DP exhibit distinct patterns of molecular expression, which can shift over the course of gestation.

Figure 5.3 The early placenta (shown here at GD8.5) consists chiefly of maternal decidua (D) and the embryonic yolk sac (YS), separated at their interface by trophoblast giant cells (arrowheads). The YS consists of visceral (inner, YS‐V) and parietal (outer, YS‐P) layers. Blood islands (BI, circled in inset of Panel (a)) form in the YS‐V as the source of primitive hematopoietic cell precursors. The YS‐P rests atop Reichert's membrane, a rodent‐specific tough basement membrane that is not visible here. The allantois (A) is a mesodermal projection (i.e. the nascent umbilical cord) connecting the caudal end of the embryo proper to the flat, broad epithelial plate known as the chorion (C), which forms centrally at the base of the embryonic placenta. The amnion (Am) is a thin membrane that eventually will envelop the entire embryo. Short arrows (in (b)) indicate large embryonic blood vessels in the chorion that connect to umbilical cord blood vessels. Abbreviations: AmC = amniotic cavity, YSC = yolk sac cavity. Stain: H&E.

Sources: Bolon [96] with permission of Elsevier, and Bolon and Ward [39] with permission of CRC Press.

Figure 5.4 The definitive placenta forms fully by GD12.5 (Panel (a)), appearing while intact as a discoid, highly vascularized mass capping the mesometrial pole of the thin, highly vascularized, translucent yolk sac (YS). After dissection (Panel (b)), the discoid cap at GD12.5 may be seen to consist of three concentric zones: the chorion (C) centrally, to which the umbilical blood vessels (arrows) are anchored; labyrinth (L); and decidua (D). Microscopically when viewed in mid‐axial cross‐section (Panel (c)), the definitive placenta at GD12.5 displays many cytoarchitecturally distinct structures, the chief of which are the labyrinth, junctional zone (comprised of the spongiotrophoblast [ST] and trophoblast giant cell [TG] layers), and decidua. Other abbreviation: YS‐V = visceral portion of the yolk sac. Stain (Panel (c)): H&E.

Sources: Ward and Devor‐Henneman [44] with permission of Iowa State University Press, and Bolon and Ward [39] with permission of CRC Press.

Figure 5.5 The labyrinth of the placenta (shown here for wild‐type CD‐1 mice) evolves over time. Early in development (GD8.5, in (a)), this zone consists of dense trophoblast cords separated by large, trophoblast‐lined maternal blood spaces (MBS or “sinusoids”) that are packed with non‐nucleated red blood cells (RBCs). In mid‐gestation (GD13.5, in (b)), the definitive placenta exhibits many tortuous, thin‐walled, closely apposed vascular channels, of two kinds: embryonic blood spaces (EBS) lined by endothelial cells and containing a mixture of primitive (large‐diameter, nucleated) and definitive (small‐diameter, non‐nucleated) RBCs, and MBS lined by three embryo‐derived trophoblast layers but not endothelium and containing only definitive RBCs. Near term (GD17.5, in (c)), both EBS and MBS contain large numbers of definitive RBCs. Stain: H&E.

Source: Bolon and Ward [39] with permission of CRC Press.

The maternal immune response against the embryo is restrained by the presence of a transient immune‐modulating structure in the decidua of mice and rats designated variously as the decidualized mesometrial triangle, mesometrial lymphoid aggregates of pregnancy (MLAp), or metrial gland (Figure 5.6) [49–52]. This metrial “gland” isn't really a gland but an area of the placenta composed of arteriolar‐like blood vessels and abundant uterine natural killer (uNK) cells (also called granulated metrial gland [GMG] cells). These uNK cells are maternal bone marrow‐derived, perforin‐positive leukocytes that express NK cell biomarkers [52, 53]. The uNK cell population and the entire metrial gland begin to regress by mid‐gestation.

Placental size differs among mouse strains. Outbred ICR (Institute of Cancer Research) mice have placentas that are about 25% larger than those of age‐matched inbred C57BL/6J (B6) mice. This discrepancy is correlated with embryonic growth as ICR embryos are approximately 25% bigger than age‐matched B6 embryos [54]. A similar placental size increase of 20% has been reported in hybrid mice, where embryos are larger relative to those generated by the inbred C57BL/Mcl or C3H/BiMcl parental strains [55], and even larger increases have been described in cloned mice [56]. Strain differences in placental biology are not limited to structural effects, as metabolic capacities and pathways in placental tissue also vary among mouse strains [57].

Figure 5.6 The nascent metrial gland (also designated the mesometrial lymphoid aggregate of pregnancy), shown here at GD8.5 (Panel (a)), appears as a dense collection of granulated metrial gland (GMG) cells (Panel (b); also called uterine natural killer [uNK] cells, Panel (c)) that surrounds large maternal blood vessels in the mesometrial decidua. Lectin histochemistry for the uNK cell marker Dolichos biflorus agglutinin (DBA) lectin (Panels (a) and (c)). Stain (panel (b)): H&E.

Sources: Dr. Bruno Zavan, University of Alfenas, Brazil, and from Bolon [96] with permission of Elsevier.