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Susan J Fisher

Publications and source records attributed to Susan J Fisher.

31 records · Page 2Linked to original sources
PubMed2004

Reciprocal chemokine receptor and ligand expression in the human placenta: implications for cytotrophoblast differentiation.

At the onset of pregnancy, the human placenta, which forms the interface between the embryo/fetus and the mother, must rapidly develop into a life-sustaining organ. The many unusual processes entailed in placental development include the poorly understood phenomenon of maternal tolerance of the hemiallogeneic cells of the conceptus, including, most remarkably, placental trophoblasts that invade the uterine wall. To investigate whether this fetal organ exerts control over the maternal immune system at the level of leukocyte trafficking, we examined placental expression of chemokines, well-known cytokine regulators of leukocyte movements. In situ hybridization revealed abundant expression of 13 chemokines in the stromal but not the trophoblast compartment of chorionic villi. Potential roles for these molecules include recruitment of the resident macrophage (Hofbauer cell) population to the villi. In parallel, cytotrophoblast production of a panel of nine chemokine receptors was assessed by using RNase protection assays. The numerous receptors detected suggested the novel possibility that the paracrine actions of chemokine ligands derived from either the villous stroma or the decidua could mediate general aspects of placental development, with specific contributions to cytotrophoblast differentiation along the pathway that leads to uterine invasion.

Cell Differentiation↗
PubMed2004

Abnormal placentation and the syndrome of preeclampsia.

Preeclampsia, particularly the severe cases that occur early in pregnancy, is associated with defects in the (placental) cytotrophoblast differentiation pathway that leads to uterine invasion. At a morphologic level, interstitial invasion often is shallow. Perhaps more significantly, endovascular invasion, particularly the arterial component, is rudimentary. The latter defect is thought to lead to hypoperfusion of the placenta. At a molecular level, these defects are associated with particular deficits in the differentiation process whereby cytotrophoblasts--epithelial cells of ectodermal origin--assume vascular-like properties. Until recently, the question was how the latter defects could lead to the maternal symptoms of this condition. Now a possible link in the form of preeclampsia-associated changes in placental production of vasculogenic/angiogenic substances and their inhibitors has been discovered. It is likely that this new paradigm will improve both diagnosis and treatment of this life-threatening pregnancy complication.

Cell Differentiation↗
PubMed2004

Listeriosis in the pregnant guinea pig: a model of vertical transmission.

Feto-placental infections represent a major cause of pregnancy complications, and yet the underlying molecular and cellular mechanisms of vertical transmission are poorly understood. Listeria monocytogenes, a facultative intracellular pathogen, is one of a group of pathogens that are known to cause feto-placental infections in humans and other mammals. The purpose of this study was to evaluate possible mechanisms of vertical transmission of L. monocytogenes. Humans and guinea pigs have a hemochorial placenta, where a single layer of fetally derived trophoblasts separates maternal from fetal circulation. We characterized L. monocytogenes infection of the feto-placental unit in a pregnant guinea pig model and in primary human trophoblasts and trophoblast-derived cell lines. The clinical manifestations of listeriosis in the pregnant guinea pigs and the tropism of L. monocytogenes to the guinea pig placenta resembled those in humans. Trophoblast cell culture systems were permissive for listerial growth and cell-to-cell spread and revealed that L. monocytogenes deficient in internalin A, a virulence factor that mediates invasion of nonphagocytic cells, was 100-fold defective in invasion. However, crossing of the feto-placental barrier in the guinea pig model was independent of internalin A, suggesting a negligible role for internalin-mediated direct invasion of trophoblasts in vivo. Further understanding of vertical transmission of L. monocytogenes will help in designing more effective means of treatment and disease prevention.

Animals↗
PubMed2004

Trophoblast differentiation during embryo implantation and formation of the maternal-fetal interface.

Trophoblasts, the specialized cells of the placenta, play a major role in implantation and formation of the maternal-fetal interface. Through an unusual differentiation process examined in this review, these fetal cells acquire properties of leukocytes and endothelial cells that enable many of their specialized functions. In recent years a great deal has been learned about the regulatory mechanisms, from transcriptional networks to oxygen tension, which control trophoblast differentiation. The challenge is to turn this information into clinically useful tests for monitoring placental function and, hence, pregnancy outcome.

Animals↗
PubMed2003

Human cytotrophoblasts promote endothelial survival and vascular remodeling through secretion of Ang2, PlGF, and VEGF-C.

Cytotrophoblasts are specialized epithelial cells of the human placenta that differentiate to acquire tumor-like properties that allow them to invade the uterus. Concurrently, they develop endothelial-like characteristics. This transformation allows cytotrophoblasts to replace the maternal cells that line uterine vessels, thereby diverting maternal blood to the placenta. Previously, we showed that invading cytotrophoblasts secrete VEGF-C and PlGF, factors that regulate their acquisition of an endothelial-like phenotype. Here, we examined the cells' expression of angiopoietin ligands and their Tie receptors. The data show that cytotrophoblasts predominantly expressed Ang2. We also studied the paracrine functions of Ang2 and the VEGFs by culturing uterine microvascular endothelial cells in cytotrophoblast-conditioned medium, which supported their growth. Removal of VEGF-C, PlGF, and/or Ang2 from the medium caused a marked reduction in cell number due to massive apoptosis. We also assayed the angiogenic potential of cytotrophoblast-derived factors in the chick chorioallantoic membrane assay. The results showed that they stimulated angiogenesis to a level comparable to that of basic FGF. These data suggest that invasive human cytotrophoblasts use an unusual repertoire of factors to influence the angiogenic state of maternal blood vessels and that this cross talk plays an important part in the endovascular component of uterine invasion.

Angiopoietin-2↗
PubMed2003

Trophoblast L-selectin-mediated adhesion at the maternal-fetal interface.

Trophoblast adhesion to the uterine wall is the requisite first step of implantation and, subsequently, placentation. At the maternal-fetal interface, we investigated the expression of selectin adhesion systems that enable leukocyte capture from the bloodstream. On the maternal side, human uterine epithelial cells up-regulated selectin oligosaccharide-based ligands during the window of receptivity. On the fetal side, human trophoblasts expressed L-selectin. This ligand-receptor system was functional, because beads coated with the selectin ligand 6-sulfo sLe(x) bound to trophoblasts, and trophoblasts bound to ligand-expressing uterine luminal epithelium in tissue sections. These results suggest that trophoblast L-selectin mediates interactions with the uterus and that this adhesion mechanism may be critical to establishing human pregnancy.

Animals↗
PubMed2003

Longitudinal serum concentrations of placental growth factor: evidence for abnormal placental angiogenesis in pathologic pregnancies.

OBJECTIVE: Complicated pregnancies demonstrate abnormal decidual and placental villous vasculature. We examined maternal concentrations of vascular endothelial growth factor and placental growth factor in normal pregnancies and in pregnancies that were complicated by isolated idiopathic small-for-gestational-age (SGA) newborn infants, preeclampsia alone, or preeclampsia with SGA newborn infants at the time of clinical disease and before the onset of clinical signs. STUDY DESIGN: Serum vascular endothelial growth factor and placental growth factor were measured by enzyme-linked immunosorbent assay in cross-sectional and longitudinal cohorts of pregnant nulliparous women. The results were compared by Wilcoxon tests or a mixed-models method, respectively. RESULTS: In the cross-sectional study, serum placental growth factor was reduced in abnormal pregnancy relative to control subjects (SGA newborn infants, 18 [P =.04]; preeclampsia, 20; or preeclampsia with small- for-gestational-age newborn infants, 11 [P =.0001]) as early as 15 to 19 weeks of gestation in preeclampsia with SGA newborn infants. Vascular endothelial growth factor was <30 pg/mL in all serum specimens from pregnant women. CONCLUSION: We postulate that decreased placental growth factor production results in abnormalities of placental angiogenesis through direct and indirect effects on other vasculotropic growth factors.

Adult↗
PubMed2003

The human placenta remodels the uterus by using a combination of molecules that govern vasculogenesis or leukocyte extravasation.

After fertilization, the next major hurdle for human reproduction is trophoblast differentiation, which is required for implantation, followed in lockstep by rapid assembly of these embryonic cells into a functional placenta. During this process, cytotrophoblast stem cells invade the uterus, anchoring the conceptus to the mother and establishing blood flow to the placenta. Cytotrophoblast invasion is actually a differentiation process that yields cells with many unusual attributes, that is, their tumor-like ability to invade the uterus and engraft maternal blood vessels. We discovered that once cytotrophoblasts commit to invasion they turn on expression of adhesion receptors characteristic of endothelium. They also begin to express and activate matrix metalloproteinase-9. Together, these phenotypic changes facilitate invasion while enabling cytotrophoblasts to present an endothelium-like surface to maternal blood. Currently, we are trying to understand the factors that play a role in cytotrophoblast differentiation/invasion. In keeping with the vascular characteristics that differentiated cytotrophoblasts assume, our recent data suggest that the key regulators include an unusual subset of vascular endothelial growth factor family members that play important roles in conventional vasculogenesis/angiogenesis. Surprisingly, we also discovered that these cells express functional l-selectin, which mediates neutrophil rolling and tethering, under shear stress, on inflamed endothelium. Trophoblast l-selectin likely interacts with carbohydrate selectin ligands that are upregulated on uterine glandular epithelium during the window of receptivity. Together, these data suggest that differentiating cytotrophoblasts have co-opted portions not only of vasculogenesis, but also of the process that facilitates leukocyte emigration from the blood into tissues, additional evidence of these cells' amazing plasticity.

Cell Movement↗
PubMed2002

Vascular endothelial growth factor ligands and receptors that regulate human cytotrophoblast survival are dysregulated in severe preeclampsia and hemolysis, elevated liver enzymes, and low platelets syndrome.

Human placental development combines elements of tumorigenesis and vasculogenesis. The organ's specialized epithelial cells, termed cytotrophoblasts, invade the uterus where they reside in the interstitial compartment. They also line uterine arteries and veins. During invasion, ectodermally derived cytotrophoblasts undergo pseudovasculogenesis, switching their adhesion molecule repertoire to mimic that of vascular cells. Failures in this transformation accompany the pregnancy complication preeclampsia. Here, we used a combination of in situ and in vitro analyses to characterize the cell's expression of vascular endothelial growth factor (VEGF) family ligands and receptors, key regulators of conventional vasculogenesis and angiogenesis. Cytotrophoblast differentiation and invasion during the first and second trimesters of pregnancy were associated with down-regulation of VEGF receptor (VEGFR)-2. Invasive cytotrophoblasts in early gestation expressed VEGF-A, VEGF-C, placental growth factor (PlGF), VEGFR-1, and VEGFR-3 and, at term, VEGF-A, PlGF, and VEGFR-1. In vitro the cells incorporated VEGF-A into the surrounding extracellular matrix; PlGF was secreted. We also found that cytotrophoblasts responded to the VEGF ligands they produced. Blocking ligand binding significantly decreased their expression of integrin alpha1, an adhesion molecule highly expressed by endovascular cytotrophoblasts, and increased apoptosis. In severe preeclampsia and hemolysis, elevated liver enzymes, and low platelets syndrome, immunolocalization on tissue sections showed that cytotrophoblast VEGF-A and VEGFR-1 staining decreased; staining for PlGF was unaffected. Cytotrophoblast secretion of the soluble form of VEGFR-1 in vitro also increased. Together, the results of this study showed that VEGF family members regulate cytotrophoblast survival and that expression of a subset of family members is dysregulated in severe forms of preeclampsia.

Cell Differentiation↗
PubMed2002

The salivary mucin MG1 (MUC5B) carries a repertoire of unique oligosaccharides that is large and diverse.

The high-molecular-mass salivary mucin MG1, one of two major mucins produced by human salivary glands, plays an important role in oral health by coating the tooth surface and by acting as a bacterial receptor. Here this mucin was purified from the submandibular/sublingual saliva of a blood group O individual. The presence of MUC5B as the major mucin in this preparation was confirmed by amino acid analysis and its reactivity with the monoclonal antibody PAN H2. To structurally characterize MG1 carbohydrates the O-glycans were released by reductive beta-elimination. Nuclear magnetic resonance spectroscopy of the nonfractionated mixture showed that (1) fucose was present in blood group H, Le(a), Le(x), Le(b), and Le(y) epitopes; (2) NeuAc was mainly linked alpha 2-3 to Gal or alpha 2-6 to GalNAcol; and (3) the major internal structures were core 1 and core 2 sequences. After this preliminary analysis the released oligosaccharides were separated into neutral (56%), sialylated (26%), and sulfated (19%) fractions, with an average length of 13, 17, and 41 sugar residues, respectively. Gas chromatography-mass spectrometry and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry of mixtures of neutral and sialylated oligosaccharides revealed at least 62 neutral and 25 sialylated oligosaccharides consisting of up to 20 monosaccharide residues. These results showed that the MG1-derived oligosaccharides were much longer than those of MG2, and only a few species were found on both molecules. Thus, these two mucins create an enormous repertoire of potential binding sites for microorganisms at one of the major portals where infectious organisms enter the body.

Carbohydrate Sequence↗
PubMedDate not supplied

Disruption of oxygen-regulated responses underlies pathological changes in the placentas of women who smoke or who are passively exposed to smoke during pregnancy.

Previously, we showed that maternal smoking harms human placental development by changing the balance between cytotrophoblast (CTB) proliferation and differentiation. To understand the mechanisms involved, we studied the effects of maternal smoking and in vitro exposure of CTBs to nicotine and on CTB expression of molecules that govern cellular responses to oxygen tension: the von Hippel-Lindau tumor suppressor protein (pVHL), the hypoxia-inducible transcription factors (HIFs), and the vascular endothelial growth factors (VEGFs). We previously reported that hypoxia upregulates CTB pVHL expression (1). Here we show that in vitro exposure of CTBs to nicotine has the same effect. Maternal smoking also dysregulated CTB expression of all three molecules. Remarkably, we found that passive exposure to cigarette smoke had many of the same effects as active smoking, a graphic demonstration of the ill effects of cigarette smoke, even secondhand, on placental development. Together, these findings explain, in part, how smoking damages the placenta by altering expression of key mediators of placental development.

Abortion, Induced↗
PubMedDate not supplied

A positron-emitting internal marker for identification of normal tissue by positron emission tomography: phantom studies and validation in patients.

PURPOSE: This study evaluated in a phantom model and verified in patients with lung cancer whether the use of an internal positron-emitting labeled marker could localize a critical structure by positron emission tomography (PET) imaging and verify multimodality image registration. MATERIALS AND METHODS: An initial device and method were developed to demonstrate by dedicated PET the location of the normal esophagus in a phantom and in three patients using a column of 2-deoxy-2-[18F]fluoro-D-glucose (FDG) solution between proximal and distal gas phases in polyurethane tubing. The device was assessed for possible loss of radioactivity. PET, CT and PET-CT fusion imaging followed. RESULTS: X-rays of the marker device showed a continuous fluid column. No leakage of contents was detected. The internal marker in the phantom and in patients allowed visualization by PET of the esophagus, and verified an image registration algorithm. CONCLUSIONS: A positron-emitting internal marker was constructed, demonstrated to retain tracer, and shown to be capable of verifying an image registration algorithm and identifying a critical structure, the esophagus, by PET in a phantom and in patients.

Carcinoma, Non-Small-Cell Lung↗