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Maternal Platelets—Friend Or Foe of the Human Placenta?

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Maternal Platelets—Friend Or Foe of the Human Placenta? International Journal of Molecular Sciences Review Maternal Platelets—Friend or Foe of the Human Placenta? Gerit Moser, Jacqueline Guettler, Désirée Forstner and Martin Gauster * Division of Cell Biology, Histology and Embryology, Gottfried Schatz Research Centre for Cell Signaling, Metabolism and Ageing, Medical University of Graz, 8010 Graz, Austria; [email protected] (G.M.); [email protected] (J.G.); [email protected] (D.F.) * Correspondence: [email protected]; Tel.: +43-316-385-71896 Received: 22 October 2019; Accepted: 8 November 2019; Published: 11 November 2019 Abstract: Human pregnancy relies on hemochorial placentation, including implantation of the blastocyst and deep invasion of fetal trophoblast cells into maternal uterine blood vessels, enabling direct contact of maternal blood with placental villi. Hemochorial placentation requires fast and reliable hemostasis to guarantee survival of the mother, but also for the neonates. During human pregnancy, maternal platelet count decreases gradually from first, to second, and third trimester. In addition to hemodilution, accelerated platelet sequestration and consumption in the placental circulation may contribute to a decline of platelet count throughout gestation. Local stasis, turbulences, or damage of the syncytiotrophoblast layer can activate maternal platelets within the placental intervillous space and result in formation of fibrin-type fibrinoid. Perivillous fibrinoid is a regular constituent of the normal placenta which is considered to be an important regulator of intervillous hemodynamics, as well as having a role in shaping the developing villous trees. However, exaggerated activation of platelets at the maternal-fetal interface can provoke inflammasome activation in the placental trophoblast, and enhance formation of circulating platelet-monocyte aggregates, resulting in sterile inflammation of the placenta and a systemic inflammatory response in the mother. Hence, the degree of activation determines whether maternal platelets are a friend or foe of the human placenta. Exaggerated activation of maternal platelets can either directly cause or propagate the disease process in placenta-associated pregnancy pathologies, such as preeclampsia. Keywords: platelets; placenta; pregnancy; preeclampsia 1. Hemochorial Placentation At term, the human placenta is, by definition, “hemochorial” which means that maternal blood has direct contact with the trophoblast layer of the fetal placenta, however, before the hemochorial placenta is fully established, a number of tightly regulated developmental processes occur in the absence of maternal blood. One fundamental step is embryo implantation, which is initiated by the apposition of the blastocyst with its embryonic pole to the endometrial epithelium. As soon as the blastocyst establishes close and stable contact with the epithelium, the development of the placenta begins. Only the outer layer of the blastocyst, i.e., the trophoblast, is the precursor of the placenta, whereas, the embryoblast, umbilical cord, amnion, and embryo are derived from the inner cell mass [1]. During implantation (day six to seven post conception), the trophoblast starts to proliferate and fuse to a temporary invasive syncytiotrophoblast. Via the fusion of underlying cytotrophoblasts, the syncytiotrophoblast is continuously expanding around the embryo. This results in a spherical shaped placenta between day eight to 13 post conception (p.c.). Around day eight p.c., the first vacuoles form within the syncytiotrophoblast, which later fuse to bigger lacunae, separated by trabeculae. These lacunae are already filled with liquid (putative a mixture of glandular Int. J. Mol. Sci. 2019, 20, 5639; doi:10.3390/ijms20225639 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2019, 20, 5639 2 of 15 Int. J. Mol. Sci. 2019, 20, 5639 2 of 16 secretions,blood plasma) maternal and are blood, the andprecursor blood plasma)of the intervillous and are the space. precursor The ofunderlying the intervillous cytotrophoblasts space. The underlyingcontinuously cytotrophoblasts proliferate and, continuously at approximately proliferate day and,14 p.c., at approximately finally migrate day into 14 the p.c., trabeculae. finally migrate The intotrabeculae the trabeculae. are filled The with trabeculae mononucleated are filled with cytotrophoblasts, mononucleated covered cytotrophoblasts, with multinucleated covered with multinucleatedsyncytiotrophoblast, syncytiotrophoblast, termed primary termedvilli. Cytotrophoblasts primary villi. Cytotrophoblasts can invade out of can these invade primary out ofvilli, these as primaryextravillous villi, trophoblasts as extravillous (EVTs), trophoblasts into the (EVTs), maternal into thetissue maternal and, from tissue here and, on, from the here villous on, the stage villous of stageplacentation of placentation starts. Subsequently, starts. Subsequently, mesenchymal mesenchymal cells follow cells the follow cytotrophoblasts the cytotrophoblasts within the within primary the primaryvilli and villireplace and replacethe cytotrophoblast the cytotrophoblast core. There core. is There always is always a layer a layerof syncytiotrophoblast of syncytiotrophoblast and andcytotrophoblast, cytotrophoblast, or a or trophoblastic a trophoblastic cell cell column column between between the the mesenchymal mesenchymal cells cells and and the the maternal tissues, which are now termed secondary villi.villi. As so soonon as the the vasculogenesis vasculogenesis within the mesenchyme starts (day(day 1818 toto 2020 p.c.),p.c.), thethe secondary secondary villi villi turn turn into into tertiary tertiary villi. villi. Until Until the the end end of of the the first first trimester trimester of humanof human gestation, gestation, nearly nearly all villi all turn villi into turn tertiary into villitertiary due tovilli the distinctdue to andthe branchingdistinct and vasculogenesis branching (Figurevasculogenesis1). The latter (Figure is mainly 1). The enabledlatter is mainly by the intraplacental enabled by the low intraplacental oxygen concentration low oxygen during concentration the first trimesterduring the [2 first,3]. trimester [2,3]. Figure 1. Development of placental villi ( a) Section through a primary villus which shows a core of cytotrophoblasts covered by the syncytiotrophoblast; ( b) section through a secondarysecondary villus, which shows a core of mesenchyme covere coveredd by a two-layered two-layered trophoblast trophoblast epit epithelium,helium, consisting of of an an inner, inner, mononucleated cytotrophoblast layer, an andd the outer syncytiotrophoblast; and ( c) section through a tertiary villus which shows bloodblood capillariescapillaries inin thethe mesenchyme.mesenchyme. Intraplacental low oxygen concentration is crucial for proper placenta development and Intraplacental low oxygen concentration is crucial for proper placenta development and vasculogenesis and is the consequence of trophoblast plugs within the uterine spiral arteries, during vasculogenesis and is the consequence of trophoblast plugs within the uterine spiral arteries, during early placental development. Trophoblast plugs result from EVT invasion in the spiral arteries, which early placental development. Trophoblast plugs result from EVT invasion in the spiral arteries, which leads to conversion of the vessels, including depletion of smooth muscle cells in their wall and loss of their elastic lamina [[4–6].4–6]. This finally finally leads to a dilation of the arteries and conversion into flaccidflaccid conduits as a guarantee for a constant uteroplacentaluteroplacental bloodblood flowflow laterlater inin pregnancy.pregnancy. In parallel,parallel, EVTsEVTs also also invade invade the the decidual decidual stroma, stroma, up toup the to first the thirdfirst ofthird the myometrium,of the myometrium, uterine glands,uterine glands, veins, andveins, lymphatics. and lymphatics. The invasionThe invasion of the of decidualthe decidual stroma stroma (interstitial (interstitial EVTs) EVTs) serves serves to attachto attach the the placenta placenta to to the the uterus uterus and and interacts interacts with with the the decidual decidual stromastroma cellscells andand the immune cells. cells. Endoglandular EVT invasion enables histiotrophic nutrition to establish prior to the establishment of the uteroplacental blood flow, flow, byby connectingconnecting the uterine glands to thethe intervillous space so that the glandular secretion products can reach the early conceptusconceptus [[7,8].7,8]. Endoglandular trophoblasts replace the glandular epithelium, and thereby open the uterin uterinee glands to the intervillous space. Most Most likely, likely, the invasion of endoglandular trophoblast occurs at the edges of the developing placenta, and the rapid laterallateral extensionextension ofof thethe developing developing placenta placenta [ 9[9]] leads leads to to a a continuous continuous accession accession of of new new glands glands to theto the placenta placenta [10 [10,11].,11]. At At the the time time of of implantation, implantation, there there is is already already firstfirst contactcontact betweenbetween trophoblasttrophoblast and uterine glands [8,10]. [8,10]. In the past, discussions of of EVT EVT invasion invasion in in veins veins has has been been controversially, controversially, but it is now well described and may serve to drain debris and waste from the placentaplacenta [[12–14].12–14]. It is important to note that the EVTs areare invasive,invasive,
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