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Physiological Reviews Oct 2016Epidemiological evidence links an individual's susceptibility to chronic disease in adult life to events during their intrauterine phase of development. Biologically... (Review)
Review
Epidemiological evidence links an individual's susceptibility to chronic disease in adult life to events during their intrauterine phase of development. Biologically this should not be unexpected, for organ systems are at their most plastic when progenitor cells are proliferating and differentiating. Influences operating at this time can permanently affect their structure and functional capacity, and the activity of enzyme systems and endocrine axes. It is now appreciated that such effects lay the foundations for a diverse array of diseases that become manifest many years later, often in response to secondary environmental stressors. Fetal development is underpinned by the placenta, the organ that forms the interface between the fetus and its mother. All nutrients and oxygen reaching the fetus must pass through this organ. The placenta also has major endocrine functions, orchestrating maternal adaptations to pregnancy and mobilizing resources for fetal use. In addition, it acts as a selective barrier, creating a protective milieu by minimizing exposure of the fetus to maternal hormones, such as glucocorticoids, xenobiotics, pathogens, and parasites. The placenta shows a remarkable capacity to adapt to adverse environmental cues and lessen their impact on the fetus. However, if placental function is impaired, or its capacity to adapt is exceeded, then fetal development may be compromised. Here, we explore the complex relationships between the placental phenotype and developmental programming of chronic disease in the offspring. Ensuring optimal placentation offers a new approach to the prevention of disorders such as cardiovascular disease, diabetes, and obesity, which are reaching epidemic proportions.
Topics: Animals; Chronic Disease; Female; Fetal Development; Humans; Maternal-Fetal Exchange; Placenta; Placentation; Pregnancy; Prenatal Exposure Delayed Effects
PubMed: 27604528
DOI: 10.1152/physrev.00029.2015 -
American Journal of Obstetrics and... Oct 2015The causes of preeclampsia remain one of the great medical mysteries of our time. This syndrome is thought to occur in 2 stages with abnormal placentation leading to a... (Review)
Review
The causes of preeclampsia remain one of the great medical mysteries of our time. This syndrome is thought to occur in 2 stages with abnormal placentation leading to a maternal inflammatory response. Specific regions of the placenta have distinct pathologic features. During normal pregnancy, cytotrophoblasts emigrate from the chorionic villi and invade the uterus, reaching the inner third of the myometrium. This unusual process is made even more exceptional by the fact that the placental cells are hemiallogeneic, coexpressing maternal and paternal genomes. Within the uterine wall, cytotrophoblasts deeply invade the spiral arteries. Cytotrophoblasts migrate up these vessels and replace, in a retrograde fashion, the maternal endothelial lining. They also insert themselves among the smooth muscle cells that form the tunica media. As a result, the spiral arteries attain the physiologic properties that are required to perfuse the placenta adequately. In comparison, invasion of the venous side of the uterine circulation is minimal, sufficient to enable venous return. In preeclampsia, cytotrophoblast invasion of the interstitial uterine compartment is frequently shallow, although not consistently so. In many locations, spiral artery invasion is incomplete. There are many fewer endovascular cytotrophoblasts, and some vessels retain portions of their endothelial lining with relatively intact muscular coats, although others are not modified. Work from our group showed that these defects mirror deficits in the differentiation program that enables cytotrophoblast invasion of the uterine wall. During normal pregnancy, invasion is accompanied by the down-regulation of epithelial-like molecules that are indicative of their ectodermal origin and up-regulation of numerous receptors and ligands that typically are expressed by endothelial or vascular smooth muscle cells. For example, the expression of epithelial-cadherin (the cell-cell adhesion molecule that many ectodermal derivatives use to adhere to one another) becomes nearly undetectable, replaced by vascular-endothelial cadherin, which serves the same purpose in blood vessels. Invading cytotrophoblasts also modulate vascular endothelial growth factor ligands and receptors, at some point in the differentiation process expressing every (mammalian) family member. Molecules in this family play crucial roles in vascular and trophoblast biology, including the prevention of apoptosis. In preeclampsia, this process of vascular mimicry is incomplete, which we theorize hinders the cells interactions with spiral arterioles. What causes these aberrations? Given what is known from animal models and human risk factors, reduced placental perfusion and/or certain disease states (metabolic, immune and cardiovascular) lie upstream. Recent evidence suggests the surprising conclusion that isolation and culture of cytotrophoblasts from the placentas of pregnancies complicated by preeclampsia enables normalization of their gene expression. The affected molecules include SEMA3B, which down-regulates vascular endothelial growth factor signaling through the PI3K/AKT and GSK3 pathways. Thus, some aspects of the aberrant differentiation of cytotrophoblasts within the uterine wall that is observed in situ may be reversible. The next challenge is asking what the instigating causes are. There is added urgency to finding the answers, because these pathways could be valuable therapeutic targets for reversing abnormal placental function in patients.
Topics: Animals; Arteries; Female; Humans; Ligands; Placenta; Placentation; Pre-Eclampsia; Pregnancy; Receptors, Vascular Endothelial Growth Factor; Trophoblasts; Vascular Endothelial Growth Factors
PubMed: 26428489
DOI: 10.1016/j.ajog.2015.08.042 -
Cells Jan 2023The first studies suggesting that abnormal expression of galectins is associated with cancer were published more than 30 years ago. Today, the role of galectins in... (Review)
Review
The first studies suggesting that abnormal expression of galectins is associated with cancer were published more than 30 years ago. Today, the role of galectins in cancer is relatively well established. We know that galectins play an active role in many types of cancer by regulating cell growth, conferring cell death resistance, or inducing local and systemic immunosuppression, allowing tumor cells to escape the host immune response. However, most of these studies have focused on very few galectins, most notably galectin-1 and galectin-3, and more recently, galectin-7 and galectin-9. Whether other galectins play a role in cancer remains unclear. This is particularly true for placental galectins, a subgroup that includes galectin-13, -14, and -16. The role of these galectins in placental development has been well described, and excellent reviews on their role during pregnancy have been published. At first sight, it was considered unlikely that placental galectins were involved in cancer. Yet, placentation and cancer progression share several cellular and molecular features, including cell invasion, immune tolerance and vascular remodeling. The development of new research tools and the concomitant increase in database repositories for high throughput gene expression data of normal and cancer tissues provide a new opportunity to examine the potential involvement of placental galectins in cancer. In this review, we discuss the possible roles of placental galectins in cancer progression and why they should be considered in cancer studies. We also address challenges associated with developing novel research tools to investigate their protumorigenic functions and design highly specific therapeutic drugs.
Topics: Pregnancy; Female; Humans; Placenta; Galectins; Neoplasms; Galectin 3; Placentation
PubMed: 36766779
DOI: 10.3390/cells12030437 -
Placenta Jul 2017Murine placentation requires trophoblast Notch2, while the Notch ligand, JAGGED1, is reduced in invasive trophoblasts from women with preeclampsia. However, the...
INTRODUCTION
Murine placentation requires trophoblast Notch2, while the Notch ligand, JAGGED1, is reduced in invasive trophoblasts from women with preeclampsia. However, the placental cells with active Notch signaling and expression of other Notch proteins and ligands in placentation have yet to be defined. We sought to identify endothelial cell and trophoblast subtypes with canonical Notch signaling in the decidua and placenta and correlate this to expression of Notch proteins and ligands.
METHODS
Notch reporter transgenic mice were used to define canonical Notch activity and immunofluorescence staining performed to characterize expression of Notch1, 2, 3, 4 and ligands, Delta-like 4 (Dll4) and Jagged1 (Jag1) during early placentation and in the mature placenta.
RESULTS
Notch signaling is active in maternal and fetal endothelial cells and trophoblasts during early placentation and in the mature placenta. Dll4, Jag1, Notch1, and Notch4 are expressed in maternal vasculature in the decidua. Dll4, Jag1 and Notch1 are expressed in fetal vasculature in the labyrinth. Dll4, Notch2 and Notch4 are co-expressed in the ectoplacental cone. Notch2 and Notch4 are expressed in parietal-trophoblast giant cells and junctional zone trophoblasts with active canonical Notch signaling and in labyrinthine syncytiotrophoblasts and sinusoidal-trophoblast giant cells.
DISCUSSION
Canonical Notch activity and distinct expression patterns for Notch proteins and ligands was evident in endothelium and trophoblasts, suggesting Notch1, Notch2, Notch4, Dll4, and Jag1 have distinct and overlapping functions in placentation. Characterization of Notch signaling defects in existing mouse models of preeclampsia may shed light on the role of Notch in developing the preeclampsia phenotype.
Topics: Animals; Endothelial Cells; Female; Male; Mice, Inbred C57BL; Mice, Transgenic; Placentation; Pregnancy; Receptors, Notch; Trophoblasts
PubMed: 28623973
DOI: 10.1016/j.placenta.2017.04.014 -
Seminars in Reproductive Medicine Jan 2016Normal placentation during the first trimester sets the stage for the rest of pregnancy and involves a finely orchestrated cellular and molecular interplay of maternal... (Review)
Review
Normal placentation during the first trimester sets the stage for the rest of pregnancy and involves a finely orchestrated cellular and molecular interplay of maternal and fetal tissues. The resulting intrauterine environment plays an important role in fetal programming and the future health of the fetus, and is impacted by multiple genetic and epigenetic factors. Abnormalities in placentation and spiral artery invasion can lead to ischemia, placental disease, and adverse obstetrical outcomes including preeclampsia, intrauterine growth restriction, and placental abruption. Although first trimester placentation is affected by multiple factors, preconception environmental influences such as mode of conception, including assisted reproductive technologies which result in fertilization in vitro and intrauterine influences due to sex differences, are emerging as potential significant factors impacting first trimester placentation.
Topics: Causality; Epigenesis, Genetic; Female; Fertilization; Fertilization in Vitro; Fetal Development; Fetal Growth Retardation; Fetus; Gene Expression; Humans; Placenta; Placenta Diseases; Placentation; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Pregnancy Trimester, First; Reproductive Techniques, Assisted; Sex Characteristics
PubMed: 26696276
DOI: 10.1055/s-0035-1570029 -
Philosophical Transactions of the Royal... Mar 2015We here review the evolution of invasive placentation in primates towards the deep penetration of the endometrium and its arteries in hominoids. The strepsirrhine... (Review)
Review
We here review the evolution of invasive placentation in primates towards the deep penetration of the endometrium and its arteries in hominoids. The strepsirrhine primates (lemurs and lorises) have non-invasive, epitheliochorial placentation, although this is thought to be derived from a more invasive type. In haplorhine primates, there is differentiation of trophoblast at the blastocyst stage into syncytial and cellular trophoblast. Implantation involves syncytiotrophoblast that first removes the uterine epithelium then consolidates at the basal lamina before continuing into the stroma. In later stages of pregnancy, especially in Old World monkeys and apes, cytotrophoblast plays a greater role in the invasive process. Columns of trophoblast cells advance to the base of the implantation site where they spread out to form a cytotrophoblastic shell. In addition, cytotrophoblasts advance into the lumen of the spiral arteries. They are responsible for remodelling these vessels to form wide, low-resistance conduits. In human and great apes, there is additional invasion of the endometrium and its vessels by trophoblasts originating from the base of the anchoring villi. Deep trophoblast invasion that extends remodelling of the spiral arteries to segments in the inner myometrium evolved in the common ancestor of gorilla, chimp and human.
Topics: Animals; Biological Evolution; Embryo Implantation; Female; Humans; Placentation; Pregnancy; Primates; Species Specificity; Trophoblasts
PubMed: 25602074
DOI: 10.1098/rstb.2014.0070 -
Journal of Anatomy Jul 2009
Topics: Embryo Implantation; Female; Fetal Development; Humans; Placentation; Pregnancy; Pregnancy Complications; Trophoblasts
PubMed: 19563552
DOI: 10.1111/j.1469-7580.2009.01114.x -
International Journal of Molecular... Nov 2023Transforming growth factor beta (TGF-β), a multifunctional cytokine, is one of the most important inflammatory cytokines closely related to pregnancy. It plays... (Review)
Review
Transforming growth factor beta (TGF-β), a multifunctional cytokine, is one of the most important inflammatory cytokines closely related to pregnancy. It plays significant roles in hormone secretion, placental development, and embryonic growth during pregnancy. TGF-β is implicated in embryo implantation and inhibits the invasion of extraepithelial trophoblast cells. It also moderates the mother-fetus interaction by adjusting the secretion pattern of immunomodulatory factors in the placenta, consequently influencing the mother's immune cells. The TGF-β family regulates the development of the nervous, respiratory, and cardiovascular systems by regulating gene expression. Furthermore, TGF-β has been associated with various pregnancy complications. An increase in TGF-β levels can induce the occurrences of pre-eclampsia and gestational diabetes mellitus, while a decrease can lead to recurrent miscarriage due to the interference of the immune tolerance environment. This review focuses on the role of TGF-β in embryo implantation and development, providing new insights for the clinical prevention and treatment of pregnancy complications.
Topics: Pregnancy; Female; Humans; Placenta; Transforming Growth Factor beta; Trophoblasts; Placentation; Cytokines; Pre-Eclampsia
PubMed: 38069201
DOI: 10.3390/ijms242316882 -
International Journal of Molecular... Nov 2019Human pregnancy relies on hemochorial placentation, including implantation of the blastocyst and deep invasion of fetal trophoblast cells into maternal uterine blood... (Review)
Review
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.
Topics: Blood Platelets; Female; Hemostasis; Humans; Placenta; Placentation; Pre-Eclampsia; Pregnancy
PubMed: 31718032
DOI: 10.3390/ijms20225639 -
International Journal of Molecular... Jun 2020With establishment of uteroplacental blood flow, the perfused fetal chorionic tissue has to deal with fluid shear stress that is produced by hemodynamic forces across... (Review)
Review
With establishment of uteroplacental blood flow, the perfused fetal chorionic tissue has to deal with fluid shear stress that is produced by hemodynamic forces across different trophoblast subtypes. Amongst many other cell types, trophoblasts are able to sense fluid shear stress through mechanotransduction. Failure in the adaption of trophoblasts to fluid shear stress is suggested to contribute to pregnancy disorders. Thus, in the past twenty years, a significant body of work has been devoted to human- and animal-derived trophoblast culture under microfluidic conditions, using a rather broad range of different fluid shear stress values as well as various different flow systems, ranging from commercially 2D to customized 3D flow culture systems. The great variations in the experimental setup reflect the general heterogeneity in blood flow through different segments of the uteroplacental circulation. While fluid shear stress is moderate in invaded uterine spiral arteries, it drastically declines after entrance of the maternal blood into the wide cavity of the intervillous space. Here, we provide an overview of the increasing body of evidence that substantiates an important influence of maternal blood flow on several aspects of trophoblast physiology, including cellular turnover and differentiation, trophoblast metabolism, as well as endocrine activity, and motility. Future trends in trophoblast flow culture will incorporate the physiological low oxygen conditions in human placental tissue and pulsatile blood flow in the experimental setup. Investigation of trophoblast mechanotransduction and development of mechanosome modulators will be another intriguing future direction.
Topics: Cell Culture Techniques; Cell Differentiation; Cell Movement; Female; Humans; Placental Circulation; Placentation; Pregnancy; Trophoblasts
PubMed: 32630006
DOI: 10.3390/ijms21134666