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The Placenta and Fetal Membranes 부산백병원 산부인과 R1. 조인호 Fetal Tissues of the FetalMaternal Communication System • The extravillous and villous traphoblasts – Placental arm • The fetal membranes (the amnion-chorion leave) – Paracrine arm • Human placenta : hemochorioendothelial type Early Human Development • • • • • • • Zygote Blastomeres Morula Blastocyst Embryo Fetus Conceptus Fertilization of the Ovum and Cleavage of the Zygote • Moore, fig3-5 • 58-cell blastocyst • 107-cell blastocyst • Fig 5-1 • Implantation – Moore, fig 3-4 • Biology of trophoblast – Trophoblast is the most variable in structure, function and development • invasiveness provides for attatchment of blastocyst to decidua of uterine cavity • nutrition of the conceptus • function as endocrine organ in human pregnancy – essential to maternal physiological adaptations & maintenance of pregnancy • Differentiation – Cellular, syncytial/ uninuclear , multinuclear • Formation of the Syncytium – Cytotrophoblasts are the cellular progenitors of the syncytiotrophoblast Cytotrophoblast Syncytiotrophoblast Morphologically uninuclear cells multinuclear giant cells cell boders well demarcated lacking single, distinct multiple & diverse present absent germinal cell cytotrophoblast nucleus miotic figure Origin • after apposition & adherence, intrusion of cytotrophoblast between endometrial epithelial cells – this process is facilitated by degradation of the extracellula matrix of endometrium /decidua catalyzed by • urokinase-type plasminogen activator • urokinase plasminogen activator receptor • multiple metalloproteinase • These functions of cytotrophoblasts invading the endometrium are indistinguishable from those of metastasizing malignant cells Immunological Acceptance of the Conceptus • Previous Theories – antigenic immaturity of the embryo-fetus – diminished immunological responsiveness of the pregnant woman – Decidua : immunologically privileged tissue site • The acceptance and the survival of conceptus in the maternal uterus must be attributed to immunological peculiarity of the trophoblasts, not the decidua Current Status of Research • Expression of the HLA system in trophoblast unique set of lymphocytes – > may provide explanation for immunological acceptance of the conceptus • 주로 trophoblast HLA expression (monomorphic HLA-G class I)과 uterine large granular lymphocyte (LGL)로 설명하 고 있다. 그러나 아직은 완전하지 않다. Immunocompetency of the Trophoblasts • Many researchers focused on the expression of the major histocompatibility complex (MHC) antigens in trophoblast – MHC class II antigens are absent from trophoblasts at all stages of gestation Trophoblast HLA Class I Expression • Normal implantation is dependent upon controlled trophoblast invasion of maternal endometrium/decidua and the spiral arteries – a mechanism for permitting and then for limitting trophoblast invasion • Such a system involves the uterine large granular lymphocytes(LGSs) and the unique expression of specific nomomeric HLA class I antigens in the trophoblasts HLA-I Gene Expression • HLA genes – the products of multiple genetic loci of the MHC within short arm of chromosome 6 – 17 class I genes have been identified • three classical genes – A, B, C => major class I(a) transplantation antigens • three other class I(b) genes – E, F, G => class I HLA antigen • HLA-G gene Uterine Large Granular Lymphocyte (LGL) • Believed to be lymphoid and of bone marrow origin and natural killer cell lineage. • Present in large numbers only at the midluteal phase of the cycle-at the expected time of implantation in the human endometrium. • Near the end of luteal phase of nonfertile ovulatory cycles, the nuclei of LGLs begin to disintegrate. • With blastocyst implantation, these cells persist in the decidua during the early weeks of pregnancy. • speculated that LGLs are involved in the regulation of trophoblast invasion. HLA-G Expression in Human Trophoblasts • HLA-G antigen – identified only in extravillous cytotrophoblast in decidua basails and chorion laeve – not present in villous trophoblast, either in syncytium or in cytotrophoblasts. – expressed in cytotrophoblast that are contiguous with maternal tissue (decidual cell) • It is hopothesized that HLA-G is immunologically permissive of antigen mismatch between mother and fetus. HLA Expression in the Human Embryo • as gestation progresses, cells from inner cell mass of blastocyst gradually develop both class I and II HLA antigen – these tissuee are not in direct contact with maternal tissue or blood Implantation and Integrin Switching • Apposition, adherence, then intrusion and invasion of the endometrium/decidua by cytotrophoblast(implantation) appears to be dependent upon – trophoblast elaboration of specific proteinases • degrade selected extracellular matrix proteins of the endometrium/decidua – coordinated and alternating process referred to as "integrin switching“ • facilitates migration and then attachment of trophoblasts in the decidua • Integrin – one of four families of cell adhesion molecules (CAMs) – cell-surface receptors that mediate the adhesion of cells to extracellular matrix proteins Trophoblast Attachment in Decidua: Oncofetal Fibronectin • onfFN(oncofetal fibronectin) – unique glycopeptide of the trophouteronectin molecule • trophouteronectin or trophoblast glue – formed by extravillous trophoblast, including those of chorion laeve – Function • a critical role for migration and attachment of the trophoblasts to maternal decidua • facilitates separation of extraembryonic tissues from the uterus at delivery Embryonic and Placental Development • Early Blastocyst – Trophoblast – hCG – Grow & expand Embryonic Development after Implantation Cytotrophoblast Invasion of Decidual Vessels • Capillary network • arterioles • Spiral arteries • Several curious features – trophoblasts in the vessels lumen do not appear to replicate – these cells are not readily dislodged by flow of blood – these cytotrophoblast appear to migrate against arterial flow and pressure – no obvious adhesion of these cells one to the other – invasion of maternal vascular tissue bt trophoblasts involves only the decidual spiral arteries, not the veins Organization of Placenta • Trophoblast Ultrastructure – Prominent microvilli of the syncytial surface (brush border) – pinocytotic vacuoles and vesicles • absorptive and secretory placental function • Chorionic Villi – 12th day에 처음 발생 – Primary villi • proliferation of cytotrophoblast extend into syncytiotrophoblast – Secondary villi • mesenchymal cord, derived from cytotrophoblast, invade solid trophoblast column – Tertiary villi • after angiogenesis occurs from the mesenchymal cores in situ – 17th day에 fetal blood vessels are functional & placental circulation이 establish됨. • Characteristic of development of H-mole – some villi, in which absence of angiogenesis results in a lack of circulation, may distended with fluid and form vesicles • Placental Cotyledons – Certain villi of the chorion frondosum extend from chorionic plate to the decidua and serve as anchoring villi – Each of the main stem villi(truncal) and their ramifications (rami) constitute a placental cotyledon (lobe) – For each cotyledon, a 1:1:1 ratio of artery to vein to cotyledon • Breaks in the Placental " Barrier“ – Numerous findings of passage of cells between mother and fetus in both directions • ex) erythroblastosis fetalis – A few fetal blood cells are found in the mother's blood – Fetal leukocytes may replicate in the mother and leukocyte s bearing a Y chromosome have been identified in women for up to 5 years after giving birth to a son • Placetal Size and Weight – Total number of cotyledons remains the same throughout gestation – Individual cotyledones continue to grow – Placental weights vary considerably • Placental Aging – As villi continue to branch and terminal ramifications become more numerous and smaller • > volume and prominence of cytotrophoblasts decrease – As syncytium thins and forms knots • > vessels become more prominent and lie closer to the surface – The stroma of the villi • in early pregnancy – branching connective ts. cells are seperated by abundant loose intercellular matrix • later – stroma becomes denser, and the cells more spindly and – Histologic changes that accompany placental growth and aging are suggestive of increase in the efficiency of transport to and exchange to meet increasing fetal metabolic requirements • • • • decrease in thickness of the syncytium partial reduction of cytotropholastic cell decrease in the stroma increase in the number of capillaries and approximation of these vessels to the syncytial surface – By 4 months • the apparent continuity of the cytotrophoblast is broken • the syncytium forms knots on the more numerous, – At term • Covering of villi may be focally reduced to a thin layer of syncytium with minimal connective tissue • Fetal capillaries seem to abut the tropohoblast • Villous stroma, Hofbauer cells, and cytotrophoblasts are markedly reduced • villi appear filled with thin-walled capillaries – Other changes suggestive of a decrease in the efficiency for placental exchange • thickening of the basement membrane of trophoblast capillaries • obliteration of certain fetal vessels • fibrin deposition on the surface of villi in basal and chorionic plates as well as elsewhere in the intervillous space Blood Circulation in the Mature Placenta – A section through the placenta in situ • amnion → chorion→ chorionic villi → intervillous space → decidual plate → myometrium Fetal Circulation • 2 umbilical arteries – deoxygenated, or "venous-like" blood flows to the placenta • 1 umbilical vein – with a significantly higher oxygen content • Hyrtl anastomosis • Two umbilical a. separate at the chorionic plate to supply branches to the cotyledons Maternal Circulation • Intervillous space -> chorionic plate -> vein • Spiral a. 는 수직으로, vein은 수평으로 주 행 – Ut. Contraction하면 vein차단 – Intervillous space내에 정체되어 모체와 태아 간의 물질교환 • Ramsey's concept • The principle factors regulating the flow of blood in the intervillous space – – – – arterial blood pressure intrauterine pressure pattern of uterine contraction factors that act specifically upon the arteriolar walls The Amnion • Innermost fetal membrane and is contiguous with amnionic fluid • Avascular structure • Provide almost all of the tensile strength of the fetal membranes – protect against rupture or tearing Structure • • • • • single layer of cuboidal epithelial cells basement membrane acellular compact layer fibroblast-like mesenchymal cells zona spongiosa • Missing element of human amnion – smooth muscle cell, nerves, lymphatics, blood vessels Development Amnion Cell Histogenesis • Amnion epithelial cells – derived from fetal ectoderm (embryonic disc) – active metabolically; synthesis of tissue inhibitos of metalloproteinase-1 • Amnion mesenchymal cells – derived from the embryonic mesoderm – synthesis of interstitial collagens that make up the compact layer of the amnion – highly capable of synthesizing cytokines - IL6, IL-8, MCP-1 • increased in response to bacterial toxin and IL-1 Anatomy • Reflected amnion • Placental amnion • Umbilical amnion Tensile Strength • decidua and chorion laeve are quite elastic and can expand to twice normal size during pregnancy • Amnion provides the major strength of the membrane • Tensile strength of amnion resides almost exclusively in the compact layer – composed of cross-linked interstial collagens I, III, and lesser amounts of V and VI Metabolic Functions • solute and water transport to maintain amnionic fluid homeostasis • produces a variety of bioactive compounds – vasoactive peptides, growth factors, cytokines • Amnionic Fluid – normally clear fluid that collects within the amnionic cavity increases in quantity as pregnancy advances until near term, when it normally decreases – Average volume of about 1,000 mL is found at term Umbilical Cord and related Structures • Development Structure and Function • Umbilical cord, or funis – fetal umbilicus -fetal surface of the placenta – diameter: 0.8 - 2.0 cm – average length: 55 cm (usual length: 30 100 cm) • nodulation , false knot • Extracellular matrix: Wharton's jelly