The placenta and fetal membranes separate the fetus from the endometrium , the inner layer of the uterine wall. An interchange of substances, such as nutrients and oxygen, occurs between the maternal and fetal bloodstreams through the placenta. The vessels in the umbilical cord connect the placental circulation with the fetal circulation. The fetal membranes include the chorion , amnion , umbilical vesicle , and allantois .
Placenta
The placenta is a fetomaternal organ that has two components ( Fig. 7.1 ):
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A fetal part that develops from the chorionic sac, the outermost fetal membrane
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A maternal part that is derived from the endometrium, the innermost layer of the uterine wall
The placenta and umbilical cord form a transport system for substances passing between the mother and embryo/fetus . Nutrients and oxygen pass from the maternal blood through the placenta to the embryo/fetal blood, and waste materials and carbon dioxide pass from the fetal blood through the placenta to the maternal blood. The placenta and fetal membranes perform the following functions and activities: protection, nutrition, respiration, excretion of waste products, and hormone production. Shortly after birth, the placenta and membranes are expelled from the uterus as the afterbirth .
Decidua
The decidua 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 after parturition (childbirth). The three regions of the decidua are named according to their relation to the implantation site (see Fig. 7.1 ):
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The decidua basalis is the part of the decidua deep to the conceptus which forms the maternal part of the placenta.
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The decidua capsularis is the superficial part of the decidua overlying the conceptus.
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The decidua 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 form decidual cells . These cells enlarge as glycogen and lipid accumulate in their cytoplasm .
The cellular and vascular changes occurring in the endometrium as the blastocyst implants constitute the decidual reaction . Many decidual cells degenerate near the chorionic sac in the region of the syncytiotrophoblast (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 (see Chapter 3 , Fig. 3.7 ).
Development of Placenta
Early development is characterized by rapid proliferation of the trophoblast and development of the chorionic sac and chorionic villi (see Chapters 3 and 4 ). Homeobox genes ( HLX, MSX2, and DLX3 ) expressed in the trophoblast and its blood vessels induce trophoblastic invasion and regulate placental development. By the end of the third week, the anatomical arrangements necessary for physiologic exchanges between the mother and embryo/fetus are established. A complex vascular network is established in the placenta by the end of the fourth week, which facilitates maternal−embryonic exchanges of gases, nutrients, and metabolic waste products.
Chorionic villi cover the entire chorionic sac until the beginning of the eighth week ( Figs. 7.2 and 7.3 , and see Fig. 7.1 C ). As the chorionic sac grows, the villi associated with the decidua capsularis become compressed, so the blood supply to them is reduced; hence, they soon degenerate (see Figs. 7.1 D and 7.3 B ). This produces a relatively avascular bare area, the smooth chorion (chorion laeve). As those villi disappear, the villi associated with the decidua basalis rapidly increase, branch profusely, and enlarge. This forms the bushy area of the chorionic sac, the villous chorion (chorion frondosum).
The size of the chorionic sac is useful in determining the gestational age of the embryo/fetus in patients with uncertain menstrual histories. The growth of the chorionic sac is extremely rapid between weeks 5 and 10. Ultrasound machines equipped with endovaginal transducers enable ultrasonographers to view the chorionic sac when it has a median sac diameter of 2 to 3 mm (see Chapter 3 , Fig. 3.7 ). Chorionic sacs with this diameter indicate that the gestational age is 31 to 32 days, which is approximately 18 days after fertilization.
The uterus, chorionic sac, and placenta enlarge as the embryo/fetus grows. Growth in the size and thickness of the placenta continues rapidly until the fetus is approximately 18 weeks old. The fully developed placenta covers 15% to 30% of the decidua of the endometrium of the uterus and weighs approximately one sixth as much as the fetus. At term, for its own metabolic requirements, the placenta uses 40% to 60% of the oxygen and glucose that reaches the uterus.
The placenta has two parts ( Fig. 7.4 , and see Fig. 7.1 E and F ):
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The fetal part is formed by the villous chorion . The chorionic villi that arise from the chorion project into the intervillous space containing maternal blood (see Fig. 7.1 D ).
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The maternal part is formed by the decidua basalis , the part of the decidua related to the fetal component of the placenta (see Fig. 7.1 C to F ). By the end of the fourth month, the decidua basalis is almost entirely replaced by the fetal part of the placenta.
The fetal part is attached to the maternal part of the placenta by the cytotrophoblastic shell , the external layer of trophoblastic cells on the maternal surface of the placenta ( Fig. 7.5 ). The chorionic villi attach firmly to the decidua basalis through the cytotrophoblastic shell, which anchors the chorionic sac to the decidua basalis. Endometrial arteries and veins pass freely through gaps in the cytotrophoblastic shell and enter the intervillous space.
The shape of the placenta is determined by the persistent area of chorionic villi (see Fig. 7.1 F ). Usually this is a circular area, giving the placenta a discoid shape. As the chorionic villi invade the decidua basalis, decidual tissue is eroded to enlarge the intervillous space (see Fig. 7.4 ). This erosion produces several wedge-shaped areas of decidua, the placental septa , which project toward the chorionic plate , the part of the chorionic wall related to the placenta ( Fig. 7.5 ). The septa divide the fetal part of the placenta into irregular convex areas, or cotyledons . Each cotyledon consists of two or more stem villi and many branch villi ( Fig. 7.6 A , and see Fig. 7.5 ). By the end of the fourth month, the decidua basalis is almost entirely replaced by cotyledons (see Fig. 7.11 ). Expression of kinase genes ( MAP2K1 and MAP2K2 ) and the transcription factor Gcm1 (glial cells missing-1) in trophoblast stem cells regulate the branching process of the stem villi to form the vascular network in the placenta.
The decidua capsularis , the layer of decidua overlying the chorionic sac, forms a capsule over the external surface of the sac (see Fig. 7.1 A to D ). As the conceptus enlarges, the decidua capsularis bulges into the uterine cavity and becomes greatly attenuated. Eventually the decidua capsularis contacts and fuses with the decidua parietalis on the opposite wall, thereby slowly obliterating the uterine cavity (see Fig. 7.1 E and F ). By 22 to 24 weeks, the reduced blood supply to the decidua capsularis causes it to degenerate and disappear.
After the disappearance of the decidua capsularis, the smooth part of the chorionic sac (smooth chorion) fuses with the decidua parietalis (see Fig. 7.1 F ). This fusion can be separated and usually occurs when blood escapes from the intervillous space (see Fig. 7.4 ). The collection of blood (hematoma) pushes the chorionic membrane away from the decidua parietalis, thereby reestablishing the potential space of the uterine cavity.
Initially, when trophoblastic cells invade the spiral arteries, these cells create plugs within the arteries. These plugs allow only maternal plasma to enter the intervillous space. As a result, there is a net negative oxygen gradient created; it has been shown that elevated oxygen levels during the early stages of development can cause complications. However, by 11 to 14 weeks, the plugs begin to break down, maternal whole blood begins to flow, and oxygen concentrations increase.
The intervillous space of the placenta , which by 11 to 14 weeks contains maternal blood, is derived from the lacunae (small spaces) that developed in the syncytiotrophoblast during the second week of development (see Chapter 3 , Fig. 3.2 A and B ). This large blood-filled space results from the coalescence and enlargement of the lacunar networks . The intervillous space is divided into compartments by placental septa; however, there is free communication between the compartments because the septa do not reach the chorionic plate (see Fig. 7.5 ).
Maternal blood enters the intervillous space from the spiral endometrial arteries in the decidua basalis (see Figs. 7.4 and 7.5 ). The spiral arteries pass through gaps in the cytotrophoblastic shell and discharge blood into the intervillous space. This large space is drained by endometrial veins , which also penetrate the cytotrophoblastic shell. These veins are found over the entire surface of the decidua basalis.
The numerous branch villi , arising from stem villi , are continuously showered with maternal blood that circulates through the intervillous space (see Figs. 7.4 and 7.5 ). The blood in this space carries oxygen and nutritional materials that are necessary for fetal growth and development. The maternal blood also contains fetal waste, carbon dioxide, salts, and products of protein metabolism.
The amniotic sac enlarges faster than the chorionic sac. As a result, the amnion and smooth chorion fuse to form the amniochorionic membrane (see Figs. 7.4 and 7.5 ). This composite membrane fuses with the decidua capsularis and, after the disappearance of the latter, adheres to the decidua parietalis (see Figs. 7.1 F , 7.4, and 7.5 ). It is the amniochorionic membrane that ruptures during labor. Preterm membrane rupture (i.e., at less than 37 weeks’ gestation) is the most common event leading to premature labor. Membrane rupture allows amniotic fluid to escape through the vagina.
Placental Circulation
The branch chorionic villi of the placenta provide a large surface area where materials may be exchanged across the very thin placental membrane interposed between the fetal and maternal circulations (see Figs. 7.5 to 7.6 ). It is through the branch villi, which arise from stem villi, that the main exchange of material between the mother and fetus takes place. Fetal and maternal circulations are separated by the placental membrane consisting of extrafetal tissues ( Fig. 7.7 , and see Fig. 7.6 B and C ).
Fetal Placental Circulation
Poorly oxygenated blood passes through the umbilical arteries to the placenta. At the site of attachment of the umbilical cord to the placenta, the arteries divide into several radially disposed chorionic arteries that branch freely in the chorionic plate before entering the chorionic villi (see Figs. 7.5 and 7.6 ). The blood vessels form an extensive arteriocapillary−venous system within the chorionic villi (see Fig. 7.6 A ), which brings the fetal blood extremely close to the maternal blood (see Fig. 7.7 ). This system provides a large surface area for the exchange of metabolic and gaseous products between the maternal and fetal bloodstreams.
Normally, there is no intermingling of fetal and maternal blood ; however, very small amounts of fetal blood may enter the maternal circulation when minute defects develop in the placental membrane (see Fig. 7.6 B and C ). The well-oxygenated fetal blood in the fetal capillaries passes into thin-walled veins that follow the chorionic arteries to the site of attachment of the umbilical cord. They converge here to form the umbilical vein (see Figs. 7.5 and 7.7 ). This large vessel carries oxygen-rich blood to the fetus.
Maternal Placental Circulation
The maternal blood in the intervillous space is temporarily outside the maternal circulatory system. It enters the intervillous space through 80 to 100 spiral endometrial arteries in the decidua basalis. These arteries discharge into the intervillous space through gaps in the cytotrophoblastic shell (see Fig. 7.5 ). The blood flow from the spiral arteries is pulsatile.
The entering blood is at a considerably higher pressure than that in the intervillous space, and therefore blood spurts toward the chorionic plate , which forms the “roof” of the intervillous space. As pressure dissipates, the blood flows slowly over the branch villi, allowing an exchange of metabolic and gaseous products with the fetal blood. The blood eventually returns through the endometrial veins to the maternal circulation.
The welfare of the embryo/fetus depends more on the adequate bathing of the branch villi with maternal blood than any other factor. Reductions of uteroplacental circulation result in fetal hypoxia and intrauterine growth restriction (IUGR) . Severe reductions of circulation may result in embryo/fetal death. The intervillous space of the mature placenta contains approximately 150 ml of blood, which is replenished three or four times per minute.
Placental Membrane
The placental membrane is a composite structure that consists of extrafetal tissues separating the maternal and fetal blood. Until approximately 20 weeks, the placental membrane consists of four layers (see Figs. 7.6 and 7.7 ): syncytiotrophoblast , cytotrophoblast , connective tissue of the villi , and endothelium of fetal capillaries . After the 20th week, cellular changes occur in the branch villi that result in the cytotrophoblast, in many of the villi, becoming attenuated.
Eventually cytotrophoblastic cells disappear over large areas of the villi, leaving only thin patches of syncytiotrophoblast. As a result, the placental membrane consists of three layers in most places (see Fig. 7.6 C ). In some areas, the placental membrane becomes markedly thinned and attenuated. At these sites, the syncytiotrophoblast comes into direct contact with the endothelium of the fetal capillaries to form a vasculosyncytial placental membrane .
Sometimes the placental membrane is called the placental barrier ; this is an inappropriate term because there are only a few substances, endogenous or exogenous, that are unable to pass through the membrane in detectable amounts. The placental membrane acts as a barrier only when a molecule is of a certain size, configuration, and charge, such as that of heparin (a compound occurring in the liver, lungs, and mast cells that inhibits blood coagulation). Some metabolites, toxins, and hormones, although present in the maternal circulation, do not pass through the placental membrane in sufficient concentrations to affect the embryo/fetus. Most drugs and other substances in the maternal blood plasma pass through the placental membrane and enter the fetal blood plasma (see Fig. 7.7 ). The syncytiotrophoblast free surface has many microvilli that increase the surface area for exchange between the maternal and fetal circulations. As pregnancy advances, the placental membrane becomes progressively thinner, and thus blood in many fetal capillaries is extremely close to the maternal blood in the intervillous space (see Figs. 7.6 C and 7.7 ).
During the third trimester, numerous nuclei in the syncytiotrophoblast aggregate to form multinucleated protrusions, syncytial knots (see Fig. 7.6 C ). These aggregations regularly break off and are carried from the intervillous space into the maternal circulation. Some knots lodge in capillaries of the maternal lungs, where they are rapidly destroyed by local enzyme action. Toward the end of pregnancy, eosinophilic fibrinoid material thickens on the surfaces of villi (see Fig. 7.6 C ), which appears to reduce placental transfer.
Functions of Placenta
The placenta has several main functions:
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Metabolism (e.g., synthesis of glycogen)
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Transport of gases and nutrients
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Endoc r ine secretion (e.g., human chorionic gonadotropin [hCG])
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Protection
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Excretion (fetal waste products)
These comprehensive activities are essential for maintaining pregnancy and promoting normal fetal development.
Placental Metabolism
The placenta, particularly during early pregnancy, synthesizes glycogen, cholesterol, and fatty acids, which serve as sources of nutrients and energy for the embryo/fetus. Many of its metabolic activities are undoubtedly critical for its other two major placental activities (transport and endocrine secretion). The placenta has a number of mechanisms that allow it to react to the various environmental situations (e.g., hypoxia) that may occur and minimize the impact on the fetus.
Placental Transfer
The transport of substances in both directions between the fetal and maternal blood is facilitated by the great surface area of the placental membrane. Almost all materials are transported across this membrane by one of the following four main transport mechanisms: simple diffusion, facilitated diffusion, active transport, and pinocytosis.
Passive transport by simple diffusion is usually characteristic of substances moving from areas of higher to lower concentration until equilibrium is established. In facilitated diffusion , there is transport through electrical gradients. Facilitated diffusion requires a transporter but no energy. Such systems may involve carrier molecules that temporarily combine with the substances to be transported. Active transport is the passage of ions or molecules across a cell membrane and against a gradient and requires energy. Pinocytosis is a form of endocytosis (brings substances into cells) in which the material is engulfed in a small amount of extracellular fluid. This method of transport is usually reserved for large molecules. Some proteins are transferred very slowly through the placenta by pinocytosis.
There are three other methods of transfer across the placental membrane. In the first method of transport, fetal red blood cells pass into the maternal circulation, particularly during parturition (childbirth), through microscopic breaks in the placental membrane. Labeled maternal red blood cells have also been found in the fetal circulation. Consequently, red blood cells may pass in either direction through very small defects in the placental membrane.
In the second method of transport , cells cross the placental membrane under their own power, for example, maternal leukocytes, which are involved in counteracting foreign substances and disease, and cells of Treponema pallidum , the organism that causes syphilis.
In the third method of transport , some bacteria and protozoa such as Toxoplasma gondii infect the placenta by creating lesions and then cross the placental membrane through the defects that are thus created.
Transfer of Gases
Oxygen, carbon dioxide, and carbon monoxide cross the placental membrane by simple diffusion . Interruption of oxygen transport for several minutes endangers the survival of the embryo/fetus. The placental membrane approaches the efficiency of the lungs for gas exchange . The quantity of oxygen reaching the fetus is primarily flow limited rather than diffusion limited; hence, fetal hypoxia (decreased levels of oxygen) results primarily from factors that diminish either the uterine blood flow or the embryo/fetal blood flow. Maternal respiratory failure (e.g., from pneumonia) will also reduce oxygen transport to the embryo/fetus.
Nutritional Substances
Nutrients constitute the bulk of substances transferred from the mother to the embryo/fetus. Water is rapidly exchanged by simple diffusion and in increasing amounts as pregnancy advances. Glucose produced by the mother and the placenta is quickly transferred to the embryo/fetus by facilitated (active) diffusion mediated primarily by glucose transporter 1 (GLUT-1), an insulin-independent glucose carrier. Maternal cholesterol, triglycerides, and phospholipids are transferred. Although there is transport of free fatty acids (FFAs), the amount transferred appears to be relatively small, with long-chain polyunsaturated fatty acids being the FFA transported in highest amounts.
Amino acids are actively transported across the placental membrane and are essential for fetal growth. For most amino acids, the plasma concentrations in the embryo/fetus are higher than in the mother. Vitamins cross the placental membrane and are essential for normal development. Water-soluble vitamins cross the placental membrane more quickly than fat-soluble vitamins.
Hormones
Protein hormones (e.g., insulin or pituitary hormone) do not reach the embryo/fetus in significant amounts, except thyroxine and triiodothyronine by a slow transfer. Unconjugated steroid hormones cross the placental membrane rather freely. Testosterone and certain synthetic progestins cross the placental membrane, and elevated concentrations may cause masculinization of female fetuses (see Chapter 20 , Fig. 20.41).
Electrolytes
Electrolytes are freely exchanged across the placental membrane in significant quantities, each type at its own rate. When a mother receives intravenous fluids with electrolytes, they also pass to the embryo/fetus and affect the status of water and electrolytes.
Maternal Antibodies and Proteins
The embryo/fetus produces only small amounts of antibodies because of its immature immune system . Some passive immunity is conferred on the fetus by the placental transfer of maternal antibodies. Immunoglobulin G (IgG) gamma globulins are readily transported to the fetus by transcytosis beginning at 16 weeks and reaching a peak by 26 weeks. At birth, fetal concentrations of IgG are higher than maternal concentrations. Maternal antibodies confer fetal immunity to some diseases such as diphtheria, smallpox, and measles ; however, no immunity is acquired to pertussis (whooping cough) or varicella (chickenpox). A maternal protein, transferrin , crosses the placental membrane and carries iron to the embryo/fetus. The placental surface contains special receptors for this protein.
Small amounts of fetal blood may pass to the maternal blood through microscopic breaks in the placental membrane. If the fetus is Rh positive and the mother is Rh negative, the fetal blood cells may stimulate the formation of anti-Rh antibodies by the immune system of the mother. These antibodies pass to the fetal blood and cause hemolysis (destruction) of the fetal Rh-positive blood cells and jaundice and anemia in the fetus.
Some fetuses with hemolytic disease of the neonate, or fetal erythroblastosis , fail to make a satisfactory intrauterine adjustment. They may die unless delivered early or given intrauterine, intraperitoneal, or intravenous transfusions of packed Rh-negative blood cells until after birth. Hemolytic disease of the neonate due to Rh incompatibility is relatively uncommon now because Rh(D) immunoglobulin given to the mother usually prevents the development of this disease in the fetus. Fetal anemia and consequent hyperbilirubinemia due to blood group incompatibility may still occur, although they are due to differences in other minor blood group antigens such as the Kell or Duffy group.
Waste Products
Urea (formed in the liver) and uric acid pass through the placental membrane by simple diffusion. Conjugated bilirubin (which is fat soluble) is easily transported by the placenta for rapid clearance.
Drugs and Drug Metabolites
Drugs taken by the mother can affect the embryo/fetus directly or indirectly by interfering with maternal or placental metabolism. Some drugs cause major birth defects. The amount of drug or metabolite reaching the placenta is controlled by the maternal blood level and blood flow through the placenta. Most drugs and drug metabolites cross the placenta by simple diffusion, the exception being those with a structural similarity to amino acids, such as methyldopa and some antimetabolites.
The use of drugs such as opioids (e.g., fentanyl) has become widespread in North America and is of alarming concern. In utero exposure to opioids may result in poor fetal growth, preterm birth, fetal anomalies, and neonatal abstinence syndrome.
Most drugs used for the management of labor readily cross the placental membrane. Depending on the dose and timing in relation to parturition (childbirth), these drugs may cause respiratory depression in the neonate. All sedatives and analgesics affect the fetus to some degree. Neuromuscular blocking agents given to the mother during operative obstetrics cross the placenta in only small amounts. Inhaled anesthetics can also cross the placental membrane and affect fetal breathing if given during parturition.
Infectious Agents
Cytomegalovirus, rubella virus, coxsackieviruses, and viruses associated with variola, varicella, measles, herpes, and poliomyelitis may pass through the placental membrane and cause fetal infection. In some cases, such as the rubella virus infection , severe birth defects such as cataracts may be produced. Microorganisms such as Treponema pallidum , which causes syphilis , and Toxoplasma gondii , which causes toxoplasmosis , produce destructive changes in the brain and eyes. These microscopic organisms cross the placental membrane, often causing severe birth defects and/or death of the embryo/fetus.
Placental Endocrine Synthesis and Secretion
Using precursors derived from the fetus and/or the mother, the syncytiotrophoblast of the placenta synthesizes protein and steroid hormones. The protein hormones synthesized by the placenta include :
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Human chorionic gonadotropin (hCG)
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Human chorionic somatomammotropin (human placental lactogen) (hCS)
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Human chorionic thyrotropin (hCT)
The glycoprotein hCG , similar to luteinizing hormone, is first secreted by the syncytiotrophoblast during the second week; hCG maintains the corpus luteum, preventing the onset of menstrual periods. The concentration of hCG in the maternal blood and urine increases to a maximum by the eighth week and then declines. hCS causes decreased glucose utilization and increased FFAs in the mother. hCT appears to function similarly to thyroid-stimulating hormone.
The steroid hormones synthesized by the placenta are progesterone and estrogens . Progesterone can be found in the placenta at all stages of gestation, indicating that progesterone is essential for the maintenance of pregnancy. The placenta forms progesterone from maternal cholesterol or pregnenolone. The ovaries of a pregnant woman can be removed after the first trimester without causing abortion because the placenta takes over the production of progesterone from the corpus luteum. Estrogens are also produced in large quantities by the syncytiotrophoblast.
The Placenta as an Allograft *
* The authors are grateful to Dr. Peeyush Lala, Professor Emeritus, Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada, for preparing these sections: “The Placenta as an Allograft” and “The Placenta as an Invasive Tumor-Like Structure.”
The placenta can be regarded as an allograft (a graft transplanted between genetically nonidentical individuals) with respect to the mother. The fetal part of the placenta is a derivative of the conceptus, which inherits both paternal and maternal genes. What protects the placenta from rejection by the mother’s immune system? This question remains a major biologic enigma in nature. The syncytiotrophoblast of the chorionic villi, although exposed to maternal immune cells within the blood sinusoids, lacks major histocompatibility (MHC) antigens and thus does not evoke rejection responses. However, extravillous trophoblast (EVT) cells, which invade the uterine decidua and its vasculature (spiral arteries), express class I MHC antigens. These antigens include HLA-G, which, being nonpolymorphic (class Ib), is poorly recognizable by T lymphocytes as an alloantigen, as well as HLA-C, which, being polymorphic (class Ia), is recognizable by T cells. In addition to averting T cells, EVT cells must also shield themselves from potential attack by natural killer (NK) lymphocytes and from injury inflicted by activation of complement. Maternal lymphocytes within the pregnancy-associated decidua include a high proportion (65% to 70%) of NK cells and a low proportion (10% to 12%) of T cells. Decidual or uterine NK (named as dNK or uNK) cells are distinct from peripheral blood NK cells in phenotype (CD56 high, CD94 / NKG2 high) and function in having poor cytotoxicity for EVT cells.
Multiple mechanisms appear to be in place to guard the placenta:
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Expression of HLA-G is restricted to a few tissues, including placental EVT cells. Its strategic location in the placenta is postulated to provide a dual immunoprotective role: (1) evasion of T-cell recognition owing to its nonpolymorphic nature and (2) recognition by the “killer-inhibitory receptors” on NK cells, thus turning off their killer function. The inadequacy of this hypothesis is suggested by several observations: (1) healthy individuals showing biallelic loss of HLA-G1 have been identified, indicating that HLA-G is not essential for fetoplacental survival; (2) this hypothesis does not explain why HLA-C, a polymorphic antigen, also expressed by EVT cells, does not evoke a rejection response in situ. Because both HLA-G and HLA-C were shown to have the unique ability to resist human cytomegalovirus-mediated MHC class I degradation, it is speculated that a selective location of these two antigens at the fetomaternal interface may help to withstand viral assault.
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Immunoprotection is provided locally by certain immunosuppressor molecules, such as prostaglandin E 2 , transforming growth factor (TGF)-β, and interleukin-10. Prostaglandin E 2 derived from the decidua was shown to block activation of maternal T cells as well as NK cells in situ. Indeed, the immunoregulatory function of decidual cells is consistent with their genealogy. It was shown that uterine endometrial stromal cells, which differentiate into decidual cells during pregnancy, are derived from progenitor (stem) cells that migrate from hemopoietic organs such as the fetal liver and bone marrow during ontogeny.
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Transient tolerance of the maternal T-cell repertoire to fetal MHC antigens may serve as a backup mechanism for placental immunoprotection. A similar B-cell tolerance has also been suggested.
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A trafficking of activated maternal leukocytes into the placenta or fetus is prevented by deletion of these cells triggered by apoptosis-inducing ligands present on the trophoblast.
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Based on genetic manipulation in mice, it was shown that the presence of complement regulatory proteins (Crry in the mouse, membrane cofactor protein or CD46 in the human), which can block activation of the third component of complement (C3) in the complement cascade, protects the placenta from complement-mediated destruction, which may happen otherwise because of residual C3 activation remaining after defending against pathogens. Crry gene knockout mice died in utero because of complement-mediated placental damage, which could be averted by additional knockout of the C3 gene.
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Experiments in mice revealed that the presence of the enzyme indoleamine 2, 3-deoxygenase in trophoblastic cells was critical for the immunoprotection of the allogeneic conceptus. It suppresses T-cell−driven local inflammatory responses, including complement activation. Treatment of pregnant mice with an indoleamine 2, 3-deoxygenase inhibitor, 1-methyltryptophan caused selective death of allogeneic (but not syngeneic) conceptuses because of massive deposition of complement and hemorrhagic necrosis at the placental sites.
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Numerous chemokines produced by stromal cells are known to attract T-cell immigration. In mouse pregnancy models, it was shown that T-cell immigration within the decidua was averted by epigenetic silencing of key T-cell–attracting inflammatory chemokine genes in decidual stromal cells. The epigenetic mechanism was evidenced by promoter accrual of repressive histone marks in the murine decidua.
The Placenta as an Invasive Tumor-Like Structure
The placenta in many species, including humans, is a highly invasive tumor-like structure that invades the uterus to tap into its blood supply to establish an adequate exchange of key molecules between the mother and embryo/fetus. What protects the uterus from placental overinvasion? After the development of chorionic villi, the invasive function of the placenta is provided by the subset of cytotrophoblastic cells (EVT cells), which are produced by proliferation and differentiation of stem cells located in the cytotrophoblastic layer of certain chorionic villi, the anchoring villi (see Fig. 7.5 ). They break out of the villous confines and migrate as cell columns to invade the decidua, where they reorganize as distinct subsets: a nearly continuous cell layer (cytotrophoblastic shell) separating the decidua from maternal blood sinusoids; cells dispersed within the decidua (interstitial trophoblast); multinucleate placental-bed giant cells produced by EVT-cell fusion; and endovascular trophoblast, which adopts an endothelial phenotype and invades and remodels the uteroplacental (spiral) arteries within the endometrium and a part of the myometrium. Optimal arterial remodeling (loss of tunica media and replacement of endothelium by the endovascular trophoblast) transforms them into low-resistance, high-flow tubes that facilitate steady placental perfusion with maternal arterial blood unhindered by the presence of vasoactive molecules. Inadequate EVT-cell invasion leading to poor placental perfusion underlies the pathogenesis of preeclampsia (a major hypertensive disorder associated with pregnancy in the mother) and certain forms of fetal growth restriction (FGR), whereas excessive invasion is a hallmark of gestational trophoblastic neoplasias and choriocarcinomas .
Trophoblastic stem cells have been successfully propagated from the murine (mouse) placenta but not from the human placenta. However, normal human EVT cells have been successfully propagated from first-trimester human placentas. Using these cells for functional assays in vitro, it was shown that the molecular mechanisms responsible for their invasiveness are identical to those of cancer cells, whereas their proliferation, migration, and invasiveness are stringently regulated in situ by a variety of locally produced molecules: growth factors, growth factor−binding proteins, proteoglycans, and components of the extracellular matrix. Numerous growth factors, such as epidermal growth factor, TGF-α, amphiregulin, colony-stimulating factor 1, vascular endothelial growth factor, and placental growth factor, were shown to stimulate EVT-cell proliferation and, to a smaller extent, migration and invasiveness, whereas insulin-like growth factor II and an insulin-like growth factor−binding protein, IGFBP-1, were shown to stimulate EVT-cell migration and invasiveness without affecting proliferation. Two decidua-derived molecules, TGF-β and a TGF-β–binding leucine-rich proteoglycan decorin (DCN), were shown to restrain EVT-cell proliferation, migration, and invasiveness independent of each other, whereas trophoblastic cancer (choriocarcinoma) cells were shown to be resistant to the inhibitory signals of both TGF-β and DCN. Thus, it appears that the decidua plays a dual role in uteroplacental homeostasis by providing immunoprotection of the placenta and also protection of the uterus from placental overinvasion.
