Placenta and Placental Transport Function Chapter 39 Placenta and Placental Transport Function © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

FIGURE 39. 1 A diagram of a term human placenta FIGURE 39.1 A diagram of a term human placenta. Shown are villous trees, arranged around maternal arterial blood inflow regions. P: perimetrium; M: myometrium; CL: chorion laeve; A: amnion; MZ: marginal zone between the placenta and fetal membranes with obliterated intervillous space; S: septum; J: junctional zone; BP: basal plate; CP: chorionic plate; IVS: intervillous space; UC: umbilical cord. Source: Reproduced with permission from Ref. 1. © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

FIGURE 39.2 Examples of interdigitation between the maternal and fetal tissues at the maternal–fetal interface. The type of interdigitation may be (A) folded, (B) lamellar, (C) trabecular, (D) villous, or (E) labyrinthine. M: maternal tissue or maternal blood; T: fetal trophoblast (black); C: fetal capillaries and fetal connective tissue (stroma). © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

FIGURE 39. 3 Examples of the maternal–fetal barrier in the placenta FIGURE 39.3 Examples of the maternal–fetal barrier in the placenta. Panel (A): Epitheliochorial placenta, with six layers separating the maternal and fetal blood. From left: Maternal capillary endothelium, maternal endometrial connective tissue, maternal endometrial epithelium, fetal trophoblasts, chorionic connective tissue, and fetal capillary endothelium. Panel (B): Endotheliochorial placenta, where the trophoblast is in direct contact with maternal capillary endothelium. Panel (C): Hemotrichorial, where the trophoblast is directly bathed in maternal blood. Panel (D): Hemodichorial, which is the same as (C), but with only two layers of trophoblasts. Panel (E): Hemomonchorial, which is the same as (D), but with only one layer of syncytiotrophoblast and interspersed cytotrophoblasts. © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

FIGURE 39. 4 A terminal villus, shown in cross-section FIGURE 39.4 A terminal villus, shown in cross-section. Both panels illustrate the narrow interface between the maternal and fetal compartments. Panel (A): A schematic showing the key structural elements of the syncytiotrophoblast. (Source: Reproduced with permission from Ref. 13.) Panel (B): Electron micrograph of a typical, terminal villus (magnification ×2000). Abbreviations (not all shown in the two panels): VM: vasculosyncytial membrane; MVM: microvillous membrane; S: syncytiotrophoblast; CT: cytotrophoblast; C: capillary; SI: sinusoid; H: macrophages (Hofbauer cells); R: stroma with fibroblasts; E: endothelial cell; BM: basal membrane; SK: syncytial knot. Source: Reproduced with permission from Ref. 14. © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

FIGURE 39.5 A simplified representation of the peripheral part of the mature placental villous tree, together with a typical cross-section depiction of different villous types. See text for details. Source: Reproduced with permission from Ref. 1. © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

FIGURE 39.6 Simplified drawings of stages during early human placental development. Panels (A) and (B): Prelacunar stages. Panel (C): Lacunar stage. Panel (D): Transition from lacunar to primary villous stage. Panel (E): Secondary villous stage. Panel (F): Tertiary villous stage. E: endometrial epithelium; EB: embryoblast; CT: cytotrophoblast; ST: syncytiotrophoblast; EM: extraembryonic mesoderm; CP: chronic plate; T: trabeculae and primary villi; L: maternal blood lacunas; TS: trophoblastic shell; EV: endometrial vessel; D: decidua; RF: Rohr’s fibrinoid; NF: Nitabuch’s fibrinoid; G: trophoblastic giant cell; X: extravillous cytotrophoblast; BP: basal plate; PB: placental bed; J: junctional zone; M: myometrium. © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

FIGURE 39.7 The perfusion of the human placenta at 8–9 weeks of gestation. Panel (A): Placenta in situ specimen showing villi over the entire surface of the chorionic sac. The villi are shorter over the anembryonic pole in association with the decidua capsularis (asterisk). (Source: Reproduced with permission from Ref. 89.) Panel (B): Diagrammatic representation showing the myometrium (M), decidua (D), amniotic cavity (AC), secondary yolk sac (SYS), and exocoelomic cavity (ECC). Onset of the maternal blood flow to the placenta (arrows) starts in the peripheral regions of the placenta. Source: Reproduced with permission from Ref. 90. © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

FIGURE 39.8 The blastocyst and the origin of trophoblastic cell lineage. A schematic that represents mouse embryonic day 4.5, or human embryonic day 6–7. © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

FIGURE 39.9 Ultrastructure of normal and preeclamptic syncytial microvillous plasma membrane (MVM) surface. Panel (A): Normal term syncytium showing a regular MVM. Panel (B): Syncytium from a pregnancy complicated by severe preeclampsia, showing loss of surface integrity, distorted microvilli, and shedding of debris ranging from (A) large cellular fragments containing swollen endoplasmic reticulum characteristic of apoptotic bodies, to (B) microvesicles, (C) exosomes, and (D) fine cellular material. Reproduced with permission from Ref. 139. © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

FIGURE 39.10 Properties of the placental barrier that may influence the overall transfer rate. See text for details. (1) Total effective surface area; (2) the properties of the syncytiotrophoblast microvillous plasma membrane (MVM), including passive characteristics such as lipid composition and fluidity, and expression of transporters, channels, enzymes, and receptors; (3) cytosolic binding proteins; (4) metabolic interconversion or catabolism in the cytoplasm; (5) properties of the syncytiotrophoblast basal plasma membrane (BM), including passive characteristics such as lipid composition and fluidity, and expression of transporters, channels, enzymes, and receptors; (6) transtrophoblastic channels; and (7) diffusion across the basement membrane, villous core, and capillary endothelium. ST: syncytiotrophoblast; CT: cytotrophoblast; EC: endothelial cell. © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

FIGURE 39.11 The role of the placenta in fetal pH regulation: transport of CO2 and protons. Carbon dioxide readily diffuses across the placental barrier as dissolved gas. Metabolically produced protons are eliminated across the placenta, mediated by H+–lactate cotransport in the BM, which is, in turn, mediated by MCT1, followed by extrusion of protons in exchange for sodium across the MVM and mediated by the sodium–proton exchanger (NHE). It is also possible that excitatory amino acid transporters (EAAT), which are known to co-transport Na+, H+, and anionic amino acids, contribute to the transfer of protons across the BM. MCT1: monocarboxylate transporter 1; CA: carbonic anhydrase; ST: syncytiotrophoblast; EC: endothelial cell. © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

FIGURE 39. 12 Placental calcium transport FIGURE 39.12 Placental calcium transport. Calcium is believed to enter the syncytiotrophoblast across the MVM via Ca2+-entry channels such as TRPV6. In the cytoplasm, calcium is rapidly sequestered into intracellular compartments or bound to calcium-binding proteins, such as calmodulin or calbindin, which transport calcium through the cytoplasm and buffer intracellular calcium. The plasma membrane Ca2+ ATPase, which is highly expressed and functional in the BM, is the primary mechanism for Ca2+ efflux out of the syncytiotrophoblast into the fetal circulation. TRPV6: transient receptor potential cation channel, subfamily V, member 6; ST: syncytiotrophoblast; EC: endothelial cell. © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

FIGURE 39. 13 Placental glucose transport FIGURE 39.13 Placental glucose transport. Glucose transfer across the human placenta is facilitated by glucose transporters (GLUTs; isoforms indicated by numbers) expressed in the two polarized syncytiotrophoblast plasma membranes. At term (left panel), GLUT1 is the primary glucose transporter in the placental barrier, with threefold higher expression in the MVM than in the BM. Transport across the BM is believed to be the rate-limiting step in transplacental glucose transfer. GLUT9 is also expressed in the MVM and BM; however, the functional importance of this transporter in the placenta remains to be established. In the first trimester (right panel), at least four different GLUT isoforms are expressed in the syncytiotrophoblast: GLUT1, GLUT3, GLUT4, and GLUT12, of which GLUT4 and GLUT12 are sensitive to regulation by insulin. ST: syncytiotrophoblast; EC: endothelial cell. © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

FIGURE 39. 14 A model for placental amino acid transport FIGURE 39.14 A model for placental amino acid transport. The uptake of amino acids from the maternal circulation across the MVM into the syncytiotrophoblast represents the active step of amino acid transport and is mediated by accumulative transporters (Ac) and amino acid exchangers (X). Accumulative transporters mediate cellular uptake, resulting in increased intracellular amino acid concentrations. Amino acid exchangers, on the other hand, exchange one amino acid for another, resulting in altered amino acid composition without changing the total concentration. The driving forces for the amino acid uptake mediated by accumulative transporters are the inwardly directed Na+ gradient, or the potential difference with the inside of the cell negative. Exchangers, such as System L, use the steep, outwardly directed concentration gradient of some nonessential amino acids (NEAA) to drive the uptake of essential amino acids (EAA) against their concentration gradients. In all of these cases, the energy for the uphill transport is ultimately generated by the Na+K+–ATPase. Amino acids are transferred across the BM by facilitated diffusion driven by the outwardly directed concentration gradient mediated by exchangers and efflux transporters. ST: syncytiotrophoblast; EC: endothelial cell. © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

FIGURE 39. 15 Lipid trafficking within placental trophoblasts FIGURE 39.15 Lipid trafficking within placental trophoblasts. Triglycerides are cleaved by lipases at the maternal surface of the placenta. Fatty acids are taken up into cells by fatty acid transport proteins (FATPs) and FAT/CD36. These fatty acids are then carried and directed by fatty acid binding proteins (FABPs) to intracellular targets, such as lipid droplets or the nucleus, or are shuttled to the fetal circulation. Cholesterol and lipoproteins are taken up into the syncytiotrophoblast (ST) by LDL receptors (LDLRs), LDL receptor-related proteins (LRPs), scavenger receptor A (SRA), and HDL-binding scavenger receptors B1 (SRB1s). Some cholesterol is retained in the cells and stored in lipid droplets. ATP-binding cassette (ABC) transporters ABCG1 and ABCA1 mediate cholesterol efflux to fetal capillaries (ST: syncytiotrophoblast, EC: Endothelial cells). © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

FIGURE 39. 16 Maternal supply and fetal demand: an integrated model FIGURE 39.16 Maternal supply and fetal demand: an integrated model. The placenta integrates maternal and fetal nutritional signals through intrinsic nutrient sensors, such as mammalian target of rapamycin (mTOR) signaling. These signals then regulate placental growth and nutrient transport to balance fetal demand with the ability of the mother to support pregnancy. Thus, the placenta plays a critical role in modulating maternal–fetal resource allocation, thereby affecting fetal growth and the long-term health of the offspring. See text for detailed explanation. IGF: insulin-like growth factor; PTHrp: parathyroid hormone–related peptide. Source: Reproduced with permission from Ref. 360. © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition