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PubMed1998

The transition to endoreduplication in trophoblast giant cells is regulated by the mSNA zinc finger transcription factor.

Terminal cell differentiation is usually associated with cell cycle exit. In some lineages, however, cells undergo continued rounds of DNA synthesis without intervening mitoses (endoreduplication) resulting in polyploid nuclei. This is striking in rodent trophoblast giant cells which contain up to 1000N of DNA. In Drosophila, the Escargot gene has been implicated in regulating the transition from mitotic cell cycles to endocycles during development. We found that a murine homologue, mSna, was expressed in mouse trophoblast and was downregulated during giant cell differentiation. The mSNA zinc finger protein bound to E-box DNA elements and, in transfected C3H10T1/2 fibroblasts, acted as a transcriptional repressor. The maximal repressive effect was dependent on both the zinc finger DNA-binding domain and the N-terminal, seven-amino-acid SNAG domain. Misexpression experiments in Rcho-1 trophoblast cells revealed that mSna regulates the transition from replicating precursor cells to committed giant cells: overexpression blocked, whereas antisense RNA-mediated underexpression promoted trophoblast giant cell differentiation. Overexpression of mSna in precursor cells had no effect on cell cycle kinetics, but did increase cyclin A and B levels, implying actions during G2. These effects were dependent on both the zinc finger and SNAG domains. Together, these data suggest that mSNA has an ESCARGOT-like function to repress the transcription of genes that promote the transition from mitotic to endoreduplicative cell cycles in rodent trophoblast.

Amino Acid Sequence↗
PubMed1998

Expression of adrenomedullin, a hypotensive peptide, in the trophoblast giant cells at the embryo implantation site in mouse.

Adrenomedullin (AM) is a newly discovered hypotensive peptide which is believed to play an important role for blood pressure control in the adult. Although it has been well established that a major production site of AM is vascular endothelial cells, we now show that AM is most highly expressed in trophoblast giant cells, which are derived from the conceptus and are directly in contact with maternal tissues at the implantation site. Northern blot and in situ hybridization analyses show that the AM mRNA begins to be detected just after implantation and its level peaks at 9.5 days postconception (d.p.c.) in those cells. Expression then falls dramatically after 10.5 d.p.c., coincident with the completion of the mature chorioallantoic placenta. Immunohistochemical analyses show that the AM peptide is secreted from the trophoblast giant cells into the surrounding tissues, i.e., embryo, decidua, and maternal circulation. In contrast, the expression of an AM receptor was not detected by Northern blot analyses in either embryo or trophoblast giant cells at 7 d.p.c., when the AM gene is most highly expressed in the trophoblast giant cells. This suggests that the AM produced and secreted from the embryo's trophoblast giant cells acts on the maternal tissues rather than on the embryonic tissues. Based on these results, we propose that the high production of AM may be the mechanism by which the embryos survive at the early postimplantation period by pooling maternal blood in the implantation site in order to secure nutrition and oxygen before the establishment of efficient embryo-maternal circulation through the mature placenta.

Adrenomedullin↗
PubMed2001

Retinoic acid promotes differentiation of trophoblast stem cells to a giant cell fate.

Trophoblast stem cell (TS cell) lines have the ability to differentiate into trophoblast subtypes in vitro and contribute to the formation of placenta in chimeras. In order to investigate the possible role of retinoic acid (RA) in placentation, we analyzed the effects of exogenous RA on TS cells in vitro and the developing ectoplacental cone in vivo. TS cells expressed all subtypes of the retinoid receptor family, with the exception of RARbeta, whose expression was stimulated in response to RA. TS cells treated with RA were compromised in their ability to proliferate and exhibited properties of differentiation into trophoblast giant cells. During TS cell differentiation into trophoblast subtypes induced by withdrawal of FGF4, RA treatment further illustrated its role in the specification of cell fate by the promotion of differentiation into giant cells and the suppression of spongiotrophoblast formation. Moreover, administration of RA during pregnancy resulted in the overabundance of giant cells at the expense of spongiotrophoblast cells. RA hereby acts as an extracellular signal whose potential function can be linked to specification events mediating trophoblast cell fate. Taken together with the spatial patterns of giant-cell formation and RA synthesis in vivo, these findings implicate a function for RA in giant-cell formation during placentation.

Animals↗
PubMed2001

Nodal regulates trophoblast differentiation and placental development.

Nodal has been thought to be an embryo-specific factor that regulates development, but nodal is also expressed in the mouse placenta beginning at midgestation, specifically in the spongiotrophoblasts. In an insertional null nodal mutant, not only is embryonic development disrupted, but mouse placental development is also grossly altered with the loss of the diploid spongiotrophoblasts and labyrinth and an expansion of the polyploid giant cell layer. A hypomorphic mutation in nodal results in an expansion of the giant cell and spongiotrophoblast layers, and a decrease in labyrinthine development. Expression of nodal in trophoblast cell cultures is sufficient to inhibit trophoblast giant cell differentiation, demonstrating that nodal can act directly on trophoblasts. The mechanism of nodal action includes the inhibition of junB gene transcription. These results suggest that nodal may be involved in redirecting trophoblast fate towards the midgestational expansion of the labyrinth region while maintaining the thin layer of trophoblast giant cells and the underlying layer of spongiotrophoblasts that form the boundary between the maternal and extraembryonic compartments.

Animals↗
PubMed1997

Permeability and metabolic properties of a trophoblast cell line (HRP-1) derived from normal rat placenta.

The HRP-1 cell line is derived from normal rat placenta and appears morphologically similar to and retains characteristic expression of cellular markers of labyrinthine trophoblast cells. In this study, monolayers of HRP-1 cells grown on permeable supports were evaluated as a potential in vitro system to study trophoblast transport and metabolism. The cell line was shown to express and retain functional activity of the predominant placental cytochrome P450 isozyme, CYP1A1. Additionally, the HRP-1 cells retain functional activity of angiotensin I converting enzyme and carboxypeptidase N-like enzyme, peptidases characteristic of the trophoblast. The permeation of several hydrophilic, inert markers across the HRP-1 monolayers was observed to be dependent on effective molecular size and to be passive in nature. Functional asymmetry of the HRP-1 cells was illustrated by the predominant permeation of linoleic acid in the apical-to-basolateral direction across the monolayers. Transferrin passage across HRP-1 monolayers was concentration-dependent, was bidirectional, and could be inhibited by unlabeled transferrin, features typical of the trophoblast transport system for transferrin. Collectively, these properties suggest that the HRP-1 cell line may provide a useful tool for evaluating some of the permeability and metabolic properties of the trophoblast.

Animals↗
PubMed2002

Hepatocyte growth factor induced human trophoblast motility involves phosphatidylinositol-3-kinase, mitogen-activated protein kinase, and inducible nitric oxide synthase.

Hepatocyte growth factor (HGF) increases human trophoblast motility and invasion, an effect which is abrogated when inducible nitric oxide synthase (iNOS) is inhibited. In this study we have investigated the pathways involved in the regulation of trophoblast motility. Both basal and HGF-stimulated motility of the extravillous trophoblast cell line, SGHPL-4, were inhibited in a dose-dependent manner by the phosphatidylinositol-3-kinase (PI3-kinase) inhibitor, LY294002. HGF-stimulated iNOS expression was also inhibited by LY294002 and direct activation of PI3-kinase, using the peptide 740Y-P, led to an increase in iNOS expression and cell motility. Pretreatment with rapamycin, which acts at a point distal to PI3-kinase activation, also inhibited basal and HGF-stimulated motility. Inhibition of the p42/p44 mitogen activated protein kinase (MAPK) pathway but not the p38 MAPK pathway had significant inhibitory effects on HGF-stimulated but not basal trophoblast motility. Inhibition of p42/p44 MAPK also inhibited HGF-induced iNOS expression. This data demonstrate that the PI3-kinase signaling pathway is involved in basal trophoblast motility and that both MAPK and PI3-kinase signaling pathways are important in HGF-stimulated motility and iNOS expression.

Cell Line↗
PubMed2001

Genetic origin of malignant trophoblastic neoplasms analyzed by sequence tag site polymorphic markers.

OBJECTIVE: To study the causative conception of malignant gestational trophoblastic neoplasms (GTNs), we analyzed malignant GTNs by microsatellite PCR markers. METHOD: DNAs extracted from 12 malignant GTNs were subjected to PCR for five different chromosomal locations. RESULT: Of the 7 cases after a complete mole (CM), 5 were derived from androgenesis, but the remaining 2 were from normal fertilization. Of the 5 cases after nonmolar pregnancies, 2 placental site trophoblastic tumors had alleles from both parents. Of the other 3 choriocarcinomas, 1 was from normal fertilization after spontaneous abortion but 2 originated from androgenesis, suggesting that 1 was from a CM prior to the antecedent abortion, transforming after a long interval. CONCLUSION: By combining the previous cases with these, our analysis of 39 cases demonstrated that trophoblastic neoplasms can arise from at least three different modes of origin (androgenesis, normal fertilization, and parthenogenesis), and antecedent pregnancy is not always identical to the causative conception. Placental site trophoblastic tumors might have different machinery for carcinogenesis because of the predominance of paternal and maternal contributions. In addition, a long dormancy of trophoblasts before malignant transformation, especially for those originating from normal fertilization, was also suggested.

Adult↗
PubMed1997

Toxicity of cadmium in human trophoblast cells (JAr choriocarcinoma): role of calmodulin and the calmodulin inhibitor, zaldaride maleate.

Cadmium (Cd), the heavy metal, is toxic to the placenta. The objectives of this study were to determine if Cd toxicity is due to inhibition of placental or trophoblast cell proliferation through interactions with the intracellular calcium binding protein, calmodulin (CaM). Cd can replace calcium and thus interfere with CaM's function. Also, CaM inhibitors reverse selected toxic effects of Cd. The CaM inhibitor, zaldaride maleate, was used to determine if Cd inhibits trophoblast cell proliferation through interactions with CaM. JAr choriocarcinoma cells, a neoplastic trophoblast cell line which is similar to early human trophoblast cells, were selected to study this question. Cd (20 and 40 microM) inhibits JAr cell proliferation, as measured by cell number and BrdU incorporation. Zaldaride (10 and 20 microM) inhibits proliferation to a lesser extent; 100 microM is lethal. To determine if zaldaride alters actions of Cd, zaldaride and Cd are added simultaneously. Zaldaride (20 microM) and Cd (20 microM) together inhibit proliferation less than Cd alone, thus partially protecting cells. Metallothionein is induced in cells exposed to Cd, while zaldaride does not cause induction of this cellular defense mechanism protein. To determine if Cd inhibits proliferation through alterations of cell cycle, JAr cells enriched for G0/G1 phase were exposed to 20 microM Cd, 20 microM zaldaride, or 20 microM Cd plus 20 microM zaldaride for 24 hr. Cells remain in G0/G1 following Cd exposure; cells treated with 20 microM zaldaride progress through S phase and into G2. Zaldaride and Cd together allow JAr cells to leave G1 and enter S phase, partially relieving the cycle block produced by Cd. This study demonstrates a role for calmodulin in mediating the toxicity of Cd in trophoblast cell proliferation.

Antidiarrheals↗
PubMed1990

Proteolytic activity of first trimester human placenta: localization of interstitial collagenase in villous and extravillous trophoblast.

In human placentation, events of implantation and early blastocyst development are mediated by fetal trophoblastic cells which penetrate into the maternal endometrium and myometrium. Although highly regulated in its biological behavior, trophoblast simulates a malignant neoplasm by virtue of invading the uterine wall and uterine spiral arteries and by embolizing throughout the systemic circulation. This process is at least in part dependant on the regulated production of proteolytic enzymes to degrade extracellular matrix. The most abundant extracellular protein is connective tissue type (interstitial) collagen. The uterine remodeling during the establishment of the embryo requires collagenase which catalyzes the initial step in the breakdown of collagen. This study demonstrates the presence of interstitial collagenase in villous and extravillous trophoblast of first trimester placenta using immunocytochemical methods on light microscopic and ultrastructural levels. Intracytoplasmic staining for interstitial collagenase was present in cyto- and syncytiotrophoblast covering the chorionic villi as well as in extravillous intermediate trophoblast invading spiral arteries in the placental bed. Furthermore, outgrowth cultures of chorionic villi were studied with the immunogold method. Gold labelling was associated with the cell surface of trophoblastic cells as well as with fibrillary collagen like proteins of newly synthesized extracellular matrix. We speculate that interstitial collagenase plays a role in the degradation of uterine collagen within the developing human placenta.

Cells, Cultured↗
PubMed1986

In vitro production of pregnancy-associated plasma protein-A (PAPP-A) by trophoblastic cells.

Pregnancy-associated plasma protein-A (PAPP-A) a high molecular weight glycoprotein, is found in high concentration in the maternal circulation during pregnancy. Immunohistochemically, PAPP-A can be localized in the trophoblast and in the decidua. Short term cultures of trophoblastic and decidual explants produce PAPP-A in vitro. It was thus of interest to see if long term cultures of primary monolayers of human trophoblast cells were capable of producing PAPP-A. Under our in vitro conditions, trophoblastic monolayers were producing both PAPP-A and beta hCG. During the first 3 days of culture PAPP-A levels increased in the medium whereas beta hCG levels decreased. The production of both proteins could be inhibited by cycloheximide. These results strongly suggest that the trophoblast is a source of PAPP-A in vivo.

Cells, Cultured↗
PubMed1981

Cyclic nucleotides and cellular kinetics in normal and abnormal human trophoblastic tissue.

The ability to synthesize DNA and the cell cycle of normal trophoblastic cells and the trophoblastic cells of hydatidiform moles and invasive moles were studied by the autoradiographic technique. Compared with normal trophoblast, hydatidiform moles or invasive moles had a higher ability to synthesize DNA. cAMP tended to inhibit DNA synthesis in normal and molar tissue, whereas cGMP tended to promote it. The cell cycle time for each type of trophoblastic tissue was roughly 15 h; however, as compared to normal trophoblast, the hydatidiform or invasive moles had a longer S phase and a shorter G1 phase.

Autoradiography↗
PubMed2000

Chorangioma with trophoblastic proliferation.

Only two examples of the entity of chorangiocarcinoma, in which there is a proliferation of both the vascular and epithelial components of the placental villi, have been reported in the literature. To test the hypothesis that chorangiocarcinomas are actually more common than implied by the literature, histological sections of chorangiomas were reviewed. Syncytiotrophoblast and cytotrophoblast proliferation, with nuclear atypia, similar to that found in trophoblastic neoplasia, were seen in 15 of 23 cases. Thus, 65% of chorangiomas fulfilled the diagnostic criteria to warrant re-assignment as "chorangiocarcinoma". The proliferation index of the cytotrophoblast in the tumor as measured by MIB-1 (Ki-67) immunostaining was significantly higher in "chorangiocarcinoma" than chorangioma (35.4% vs 15.7%, P<0.02). The following factors had no relationship to the presence or absence of trophoblastic proliferation: vascularity, cellularity, infarction, size or location of the chorangioma, or age of the patient. Five of the 15 chorangiomas with trophoblastic proliferation were of the chorangiomatosis variety. No formal follow-up was performed, as this was a retrospective study, but there is no recorded case of persistent gestational trophoblastic disease in this cohort, although one woman with "chorangiocarcinoma" had a history of previous hydatidiform molar pregnancies. An apparently benign clinical course is seen. These lesions, best described as chorangiomas with trophoblastic proliferation, are more common than suggested by the rarity of reported cases.

Adult↗
PubMed2000

Hyperglycaemia-induced subcellular redistribution of GLUT1 glucose transporters in cultured human term placental trophoblast cells.

AIMS/HYPOTHESIS: We have recently shown that hyperglycaemia down-regulates the GLUT1 glucose transport system of term placental trophoblast. The reduction in GLUT1 protein alone was, however, not sufficient to explain the decrease in net glucose uptake, suggesting additional mechanisms. Therefore, we hypothesised that hyperglycaemia in vitro leads to a GLUT1 translocation from the trophoblast surface to intracellular sites. METHODS: This was tested in our study by determining the subcellular distribution of GLUT1 in human term placental trophoblast (n = 5 placentas) cultured for 48 h with 5 compared with 25 mmol/l D-glucose in vitro using immunogold labelling. RESULTS: Electron microscopic examination of cell profiles showed that 73% of total GLUT1 molecules reside in the trophoblast plasma membrane under basal conditions. The reduced GLUT1 expression (-20%; p < 0.05) after culture of the cells with 25 mmol/l glucose was accompanied by an internalisation of plasma membrane GLUT1, resulting in a loss of 40% (p < 0.05) in cell surface transporter labelling. Western blotting identified a characteristically broad band between 55-65 kDa, confirming the specificity of the GLUT1 antiserum. CONCLUSION/INTERPRETATION: We postulate that in addition to down-regulating human GLUT1 protein concentrations, glucose exerts its autoregulatory effect on hexose transport in term placental trophoblast by altering GLUT1 partitioning between the plasma membrane and intracellular sites in favour of the latter.

Cell Survival↗
PubMed2003

ATP-evoked increase in intracellular calcium via the P2Y receptor in proliferating bovine trophoblast cells.

Bovine trophoblasts actively proliferate to elongate blastocysts before implantation. The trophoblast at this stage secretes cytokines and starts to differentiate into an endocrine cell (binucleate cell) for successful pregnancy. Intracellular calcium ([Ca2+]i) may act as a second messenger in the trophoblast response. In this study, we investigated [Ca2+]i signals in a bovine trophoblast cell line (BT-1) using fura-2 fluorescence. We found that an application of ATP (> or =1 microM) induced a transient increase in [Ca2+]i in BT-1 cells. The ATP-induced increase was not affected by the removal of extracellular Ca2+, but was suppressed by suramin (100 microM), an antagonist of P2 receptors. Pretreatment with pertussis toxin (0.1 or 1 microg/ml) partially inhibited the response to ATP. The order of potency to increase [Ca2+]i was ATP=UTP>ADP. ATP-induced [Ca2+]i responses preferentially occurred in cells at the periphery of the colony. The reduced responses at the center of the colony were associated with an increase in cell density and decrease in bromodeoxyuridine incorporation. These results indicated that ATP stimulated P2Y receptors coupled to pertussis toxin-sensitive and -insensitive G proteins, leading to an increase in [Ca2+]i as a result of release of Ca2+ from intracellular stores in BT-1 cells. The occurrence of ATP-induced [Ca2+]i signals depended on the cell confluence and reflected the high proliferative activity of the trophoblast cell population.

Adenosine Triphosphate↗
PubMed1986

Methotrexate inhibition of normal trophoblasts in vitro.

Methotrexate is a folic acid inhibitor useful in the treatment of gestational trophoblastic disease. Its effect on normal trophoblast in vitro was studied to help establish a minimum effective dose in vivo for the conservative treatment of ectopic pregnancy. In vitro inhibition of normal trophoblastic cell growth was measured after 48 hours of exposure to variable concentrations of methotrexate (10(-2) to 10(-9) mol/L) and rescue with leucovorin. A modification of Cotte's method of trophoblastic cell enrichment was used. Long-term (10 days) linear growth inhibition was observed at concentrations greater than 10(-5) mol/L. Leucovorin control cultures showed no inhibition of cell growth. The study demonstrates that methotrexate is effective in inhibiting normal trophoblastic cell culture growth in vitro at concentrations 1000 times those reported necessary to inhibit deoxyribonucleic acid synthesis in choriocarcinoma cell cultures.

Cell Division↗
PubMed1989

Radioimmunoassay of free beta-subunit of human chorionic gonadotropin in diagnosis of high-risk and low-risk gestational trophoblastic disease.

A radioimmunoassay was performed with monoclonal antibody 1E5, which distinguishes free beta-subunit of human chorionic gonadotropin in the presence of intact human chorionic gonadotrophin. Serum samples were obtained from 68 pregnant women, 9 with hydatidiform mole who underwent spontaneous remission, 12 with hydatidiform mole who developed gestational trophoblastic disease, 5 with metastatic gestational trophoblastic disease of high-risk category, and 1 with choriocarcinoma concomitant with pregnancy. The concentrations of free beta-subunit of human chorionic gonadotropin and total beta-subunit were determined on the sera. The assay data were expressed as a ratio of nanograms of free beta-subunit per 1000 mIU of total beta-subunit. The ratios, analyzed by the Wilcoxon two-sample test, indicated a highly significant correlation between high ratios and the eventual diagnosis of high-risk gestational trophoblastic disease (p = 0.0019). This study suggests that the excessive production of free beta-subunit of human chorionic gonadotrophin may identify patients with high-risk gestational trophoblastic disease much earlier and identify gestational trophoblastic disease in patients during pregnancy.

Adult↗
PubMed1989

Aspirin differentially affects thromboxane and prostacyclin production by trophoblast and villous core compartments of human placental villi.

Low-dose aspirin has been used as prophylactic treatment for preeclampsia and fetal growth retardation, but the physiologic mechanisms for the beneficial effect of this therapy are unknown. We studied the effects of aspirin on eicosanoid production by different compartments of normal term human placental villi. Duplicate parallel incubations (n = 7) of whole villi, villous core tissues, and trophoblast were established on Millicell platform dishes in minimum essential medium in the presence or absence of 1 x 10(-4) or 1 x 10(-5) mol/L aspirin. Production rates of thromboxane A2 and prostacyclin were estimated by radioimmunoassay of their stable hydrolysis products, thromboxane B2 and 6-keto-prostaglandin F1 alpha, respectively. Our results indicate that 1 x 10(-4) mol/L aspirin inhibits thromboxane production in whole villi and villous core tissues denuded of their trophoblast layer but not in isolated trophoblast cells. The same concentration of aspirin also inhibits prostacyclin production in the isolated villous core but not in whole villi and not in isolated trophoblast. We conclude that aspirin can selectively inhibit thromboxane production in whole placental villi and differentially affects thromboxane and prostacyclin production by the trophoblast and villous core compartments.

Aspirin↗
PubMed1990

Inhibition of aromatase activity by 8-bromo-cyclic adenosine monophosphate in cultured first-trimester human trophoblast.

We have previously shown that 8-bromo-adenosine-3':5'-cyclic monophosphate inhibits production of estradiol from androgen precursors in trophoblast isolated from term placentas. In these experiments we sought to evaluate the effect of 8-bromo-adenosine-3':5'-cyclic monophosphate on aromatase activity in first-trimester trophoblast culture. Trophoblast cells were enzyme dispersed from first-trimester placentas and purified on a Percoll gradient. On the third and fourth day after dispersion cultures were treated with androstenedione or testosterone with and without 2 mmol/L 8-bromo-adenosine-3':5'-cyclic monophosphate. The quantity of estradiol, estrone, progesterone, human placental lactogen, and human chorionic gonadotropin was determined by radioimmunoassay. We concluded that in first-trimester trophoblast, as previously reported in term trophoblast, 8-bromo-adenosine-3':5'-cyclic monophosphate inhibited the production of estradiol from the supplied androgen precursors. Human chorionic gonadotropin and human placental lactogen production was stimulated by 8-bromo-adenosine-3':5'-cyclic monophosphate. Progesterone production was either stimulated or was unchanged by the presence of 8-bromo-adenosine-3':5'-cyclic monophosphate.

8-Bromo Cyclic Adenosine Monophosphate↗