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PubMed2000

Effects of the chromatographic fractions of the pig placental trophoblast on graft-versus-host reaction.

The trophoblast has a significant role in regulation of immune reactions at the materno-fetal interface by producing biologically active substances. In our previous studies five fractions with immunomodulatory activities were isolated by gel chromatography from trophoblast of pig placentas. To confirm the immunomodulatory effect of these trophoblast fractions on allogeneic in vivo systems and to obtain more evidence for the relevance of their activity on the maternofetal interface, their effect was studied on graft-versus-host reaction (GVHR). To assess the GVHR, the primary and secondary popliteal lymph nodes assay was used in mice. In the primary GVHR, 100 microg protein of Fraction 2-5, mixed with 5 x 10(6) allogeneic spleen cells (C57BL/6), were injected into one of the foot pads of recipient (BALB/c) mice. The secondary GVHR was induced in F1 (BALB/c x C57BL/6) mice by injection of spleen cells of BALB/c mice intraperitoneally preimmunized with allogeneic cells. The GVHR was measured by the weight of lymph nodes and by the lymphocyte proliferation. Flow cytometric analyses of the cells in the nodes with GVHR and under the influence of Fraction 4 or 5 were performed using monoclonal antibodies. In the primary GVHR, Fraction 4 or 5, injected simultaneously with allogeneic spleen cells, significantly suppressed the lymph nodes reactivity. Fractions 4 and 5 inhibited the ability of the spleen cells of mice intraperitoneally preimmunized with allogeneic cells to induce secondary GVHR in F1 mice. The Fraction 2 and 3 had no effect on GVHR. The results revealed that a group of proteins with Mr 37-7 kDa, isolated from trophoblast of pig placenta, strongly suppressed popliteal lymph node reactivity in the primary and secondary GVHR. The data provide convincing evidence for these fractions in vivo activity, for their effect across the species barrier and suggest the relevance of the same reactions on the materno-fetal interface.

Animals↗
PubMedDate not supplied

Routine terminations of pregnancy--should we screen for gestational trophoblastic neoplasia?

After termination of pregnancy for non-medical reasons, the products of conception are often not routinely examined for gestational trophoblastic neoplasia. Between 1995 and 2001 we identified 15 women without and 36 women with a pathological diagnosis of gestational trophoblastic neoplasia at the time of their pregnancy termination. Women without a diagnosis were significantly more likely to have subsequent life-threatening complications of gestational trophoblastic neoplasia (four of 15 vs none of 36; p=0.003), and to require surgical intervention (15 of 15 vs one of 36; p<0.0001) and chemotherapy (nine of 15 vs two of 36; p<0.0001). All women should be screened for gestational trophoblastic neoplasia after termination of pregnancy.

Abortion, Induced↗
PubMed2003

Alpha-2 macroglobulin controls trophoblast positioning in mouse implantation sites.

In humans, functional deficiency of alpha-2M is not known, implying alpha 2M is essential for gestational success. Mice, deficient in two members of the alpha-2 Macroglobulin (alpha 2M) family, i.e. alpha-2 macroglobulin (MAM) and murinoglobulin-1 (MUG-1) are viable, fertile and phenotypically normal, unless stressed (Am J Pathol, 155 (1999), 983). Here, we analysed implantation sites in MAM(-/-)/MUG-1(-/-)mice during pregnancy, a strong physiological stressor. Despite some post-implantation fetal loss, mean litter size was comparable to congenic C57Bl/6J (B6) mice, but MAM(-/-)/MUG-1(-/-)pups were significantly lighter and the sex ratio was skewed towards males. Implantation sites appeared histologically normal up to gestational day (gd) 8. By gd 10, extensive over-development of trophoblasts was evident, accompanied by relative deficits in decidua, in the mural mesometrial lymphoid aggregates of pregnancy and in uterine Natural Killer cells. At gd 10-12, decidual spiral arteries were dilated but abnormally cuffed by trophoblasts that extended anomalously, for midgestation, to the myometrial circular smooth muscle. Ultrastructurally, trophoblasts in the mesometrial decidua made intimate contact with endothelial cells that were shedding membrane fragments. These findings demonstrate that alpha 2M, and thereby proteinases and/or cytokines whose bio-availability is regulated by alpha 2M, exert significant decidual regulation on trophoblast invasion.

Animals↗
PubMed1995

The maternal leucocyte response to the endometrial cups in horses is correlated with the developmental stages of the invasive trophoblast cells.

Invading trophoblasts form endometrial cups in the endometrium of the pregnant mare. In the present study we characterized the maternal leucocyte response to endometrial cups from their formation to their regression. The maternal leucocyte response was correlated with the stages of trophoblast development. (1) Aggregates of CD4+ and CD8+ cells were present between the migrating and differentiating endometrial cup trophoblasts and surrounding the forming endometrial cups. (2) Numbers of CD4+ cells within the mature endometrial cups were much reduced. At the periphery of the endometrial cups CD4+ and CD8+ cells were found in patchy accumulations around endometrial glands; small clusters of CD79+ B lymphocytes were present as well. (3) Scattered CD4+ and CD8+ cells were found within dying endometrial cups; areas of cell death were infiltrated with neutrophils. Large aggregates of CD4+ cells and CD8+ cells, and small but numerous clusters of CD79+ cells and eosinophils, were found outside of the dying endometrial cups. The CD4+ or CD8+ cells were mostly CD3+ T cells; some were probably macrophages which can express both of these markers in horses. The correlation between the developmental stages of the endometrial cup trophoblast and the maternal leucocyte response suggests a complicated cytokine-mediated regulatory network.

Animals↗
PubMed1994

Quantitative evidence for the spatial dispersal of trophoblast nuclei in human placental villi during gestation.

A common assertion in the literature is that Langhans cells in placental villi decline in number during gestation but this is a misinterpretation which may be caused by the greater growth of villous surface area compared with trophoblast volume. To test this possibility, human placentae were collected at 12-41 weeks of gestation for a cross-sectional study on the packing density of nuclei within villous trophoblast. Numbers of nuclei in the cyto- and syncytiotrophoblast were estimated using a design-based stereological device, the physical disector (parallel pairs of sections). Surface areas were estimated in order to assess the overall growth of villous arborizations. Packing densities of nuclei were calculated and expressed as numbers/1000 microns 2 of villous surface. Densities decreased during gestation and this can be explained by expansion of villous surface area and thinning of trophoblast. The biggest drop in packing density of cytotrophoblast nuclei (30 per cent) occurred between 17-21 and 22-26 weeks and this period coincided with the largest changes in villous surface area (62 per cent increase) and trophoblast thickness (30 per cent decrease). Results are consistent with the notion of an epithelial proliferative unit of constant volume and comprising about nine syncytiotrophoblast nuclei per Langhans cell.

Cell Nucleus↗
PubMedDate not supplied

Transferrin receptor expression in early postimplantation mouse trophoblast and associated tissues.

The expression of the transferrin receptor (TR) was examined on murine trophoblast cells on days 6, 8 and 10 of gestation, using a monoclonal antibody visualized by indirect immunofluorescence on cryostat sections of the implant site. In the day 6 tissues, TR were observed on both the ectoplacental cone (EPC) and mural giant cell trophoblast populations, as well as on the embryonic ectoderm, anti-mesometrial decidual cells, uterine glandular epithelium and myometrium. By the 8th day of gestation, TR expression was weak, or undetectable on trophoblast giant cells (TGC), but remained strong on the proliferating cells of the EPC and embryo. In the definitive placenta (day 10), TR are expressed primarily on the differentiated labyrinthine trophoblast cells involved in the maternal-fetal transfer of iron.

Animals↗
PubMedDate not supplied

Trophoblast cell differentiation and organization: role of fetal and ovarian signals.

The rat chorioallantoic placenta is organized into two distinct zones (junctional and labyrinth) and expresses six members of the placental prolactin (PRL) family: placental lactogen-I (PL-I), PL-I variant (PL-Iv), PL-II, PRL-like protein-A (PLP-A), PLP-B, and PLP-C. These placental hormones are expressed in distinct cell- and temporal-specific patterns and can be used to monitor the state of differentiation of rat trophoblast cells. This study was initiated to examine the role of the fetus and maternal ovaries in the regulation of trophoblast cell differentiation and organization. Expression of the placental PRL family was monitored by Northern and Western blotting and immunocytochemical analysis. The roles of the fetus and maternal ovaries were examined by chemically induced fetal death (DFX, induced by intraamniotic injection of digoxin) and surgical removal of the ovaries (OVX), respectively. The endocrine differentiation of the placenta was assessed on day 19 of gestation (sperm positive = day 0, parturition = day 21). Day 10 of gestation was the earliest day that DFX could be reliably performed. Day 10 is a time point during pregnancy preceding the onset of expression of all members of the placental PRL family except PL-I. DFX on day 10 of gestation did not affect the endocrine differentiation of the trophoblast cells but did alter the organization of the chorioallantoic placenta. PL-II, PL-Iv, and the PLPs were all expressed in their appropriate molecular forms and cell types in placentas developing in the absence of fetal influence. The maternal ovaries, in the absence of the fetus, had two distinct actions on the placenta: ovarian signals were essential during a period at midgestation for the maintenance of the placenta and exposure of the developing placenta to ovarian signals during the second half of gestation, in the absence of the fetus, arrested labyrinth zone development. The active ovarian signals were progesterone and estrogen. We conclude that trophoblast cell differentiation occurs independent of the fetus and maternal ovaries. However, signals from both the fetus and maternal ovaries are required for normal organization of the chorioallantoic placenta.

Alkaline Phosphatase↗
PubMedDate not supplied

Differential secretion of prostaglandin E and prostaglandin F2 alpha by ovine uninucleate trophoblast cells in vitro.

We have previously shown that ovine uninucleate trophoblast cells maintained in serum-free medium on Matrigel-coated filters in dual-compartment culture chambers retain morphological polarity similar to that found in vivo. The present study was undertaken to determine the time course of tight junction formation between these cells in vitro and to characterize their basal release of prostaglandin E and F2 alpha. Trophoblast cells were purified from ovine placentomes obtained at 117-124 days of gestation and maintained in culture for up to 10 days. On each day of culture, the permeability of the cell monolayers to 3H-inulin and the secretion of prostaglandin E and F2 alpha were determined. Minimum permeability of the cell monolayers was reached by day 4 of culture, indicating that tight junction formation was complete by this time. Following an initial decrease, prostaglandin release by the trophoblast cells stabilized on days 6 to 8 of culture. On these days, prostaglandin E was secreted in equal amounts into the apical and basal compartments of the culture chamber. There was, however, 3.5 times more prostaglandin F2 alpha secreted into the apical chamber than the basal chamber at this stage of culture. These findings confirm the functional polarity of ovine trophoblast cells in culture and demonstrate differential secretion of prostaglandin E and F2 alpha by these cells.

Animals↗
PubMed1996

Expression of the transporter for antigen processing-1 (Tap-1) Gene in subpopulations of human trophoblast cells.

Heterodimers of transporter for antigen processing proteins, Tap-1 and Tap-2, are essential components of the pathway that leads to expression of conventional HLA-A, -B class I transplantation antigens on cell surfaces. In this study, expression of the Tap-1 gene in trophoblast cells, some of which display novel and unconventional HLA class I molecules that include HLA-G and an HLA-C-like antigen, was investigated by using in situ hybridization to identify Tap-1 mRNA and immunohistochemistry to detect Tap-1 protein. The experiments were done on semiserial sections of paraformaldehyde-fixed tissues. In first trimester placentas, expression of the Tap-1 gene correlated with expression of HLA class I antigens in trophoblast cells. HLA-G/C positive extravillous cytotrophoblast cells exhibited high intensity in situ hybridization signals for Tap-1 mRNA and strong staining with anti-Tap-1 whereas Tap-1 gene products were rarely detected in HLA class I antigen negative syncytiotrophoblast and villous cytotrophoblast cells. Relationships were less definitive in term tissues. Although Tap-1 protein was detectable in extravillous cytotrophoblast cells (chorionic cytotrophoblast cells) as expected, HLA class I negative syncytiotrophoblast contained low intensity hybridization and immunostaining signals. Collectively, the data suggest that (1) as with conventional HLA class I antigens in other types of cells, the pathway leading to expression of novel HLA class I antigens in trophoblast cells includes transport of peptides by Tap-1, and that (2) deficiencies in Tap-1 might account in (whole or in) part for the failure of some trophoblast cells to express HLA class I antigens.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMedDate not supplied

Immunological studies of transferrin and transferrin receptors of human placental trophoblast.

In primate pregnancy, fetal iron is derived from maternal transferrin; however, the mechanisms by which iron is taken up by the human placenta have not yet been established. In the present study, transferrin was demonstrated on the microvillous surface of human trophoblast in immunohistological studies of 130 mature and immature placentae from both normal and abnormal pregnancies. Similar results were found for baboon placentae. Upon short-term culture of placental tissue, the amount of trophoblast transferrin decreased and no incorporation of 14C lysine into transferrin could be detected by radioimmunoelectrophoresis. Thus this transferrin apparently was not synthesized by the placenta. When transferrin was removed from cryostat sections of placenta by treatment with chaotropic agents, subsequently added transferrin bound in an identical distribution. The specificity of this reaction was confirmed by the lack of binding of other serum proteins and by displacement procedures in which trophoblast transferrin was shown to be dislodged by transferrin added in vitro. These findings suggest that placental iron transport is predicated by binding of transferrin to specific receptors on trophoblast.

Animals↗
PubMedDate not supplied

Trophoblast invasion and alteration of mesometrial arteries in the pregnant hamster: light and electron microscopic observations.

During gestation in the Syrian golden hamster, an extensive migration of trophoblast into the maternal uteroplacental arterial system takes place. The present light and electron microscopic study has focused on one facet of this phenomenon, namely the trophoblastic invasion and alteration of the mesometrial 'vascular knot' (a complex of anastamosing, small arterial channels carrying blood to the chorio-allantoic placenta). Beginning at about the 8th day of gestation, motile trophoblastic giant cells (TGC), originating from the primitive trophospongium (Träger), invade and migrate as a wave up the central maternal arteries of the decidua basalis. During the 12th and 13th days of gestation, they reach the mesometrium and successively settle in the lumina of the vascular knot arterial channels. Between this time and parturition (day 16) the arrested TGC sequentially remove and replace the arterial endothelium, breach the elastic lamina, and apparently destroy (by lytic activity) nearly all of the mural smooth muscle. Near term, the vascular knot arterial channels are composed almost entirely of TGC. The functional significance of these events, and, more generally, the phenomenon of trophoblastic invasion of maternal uterine arteries in mammalian species having haemochorial-type placentae, are still uncertain. These invasions may be requisite to adapting, structurally and physiologically, the maternal uterine arteries to support of the fetoplacental unit and/or to maintaining the immunologically privileged status of the latter.

Animals↗
PubMedDate not supplied

Uteroplacental arterial changes related to interstitial trophoblast migration in early human pregnancy.

Morphometric and statistical techniques were used to assess the relation of myometrial interstitial trophoblast to the uteroplacental vasculature in 27 intact hysterectomy specimens ranging from 8 to 18 weeks' gestation. It was found that the volume density of cytotrophoblast in the myometrium and in particular the proximity of such trophoblast to the placental bed spiral arteries correlated significantly with morphological alterations in these vessels. The changes included swelling of endothelium, hypertrophy of individual medial smooth muscle cells, and oedema and disruption of the architecture of the vessel wall as a time-related continuum. Some of the changes, such as swollen endothelium and basophilia of medial smooth muscle cells were noted also in spiral arteries in the non-placental bed endometrium but to a considerably less extent than in the placental bed. Intimal vacuolation was common to placental bed and non-placental bed arteries, increased with gestational age and can be considered as a non-specific feature. The migration of endovascular trophoblast into the myometrial spiral arteries in the second trimester occurred only when these arteries had been considerably altered in their morphology. These findings indicate that migratory interstitial cytotrophoblast probably has a role to play in the preparation of the myometrial segments of the uteroplacental arteries for the second wave of endovascular trophoblast migration that occurs in the second trimester of human pregnancy.

Arteries↗
PubMedDate not supplied

Partial characterization of an immortalized human trophoblast cell-line, TCL-1, which possesses a CSF-1 autocrine loop.

Many previous studies in both mouse and human placenta have implicated a role for colony stimulating factor-1 (CSF-1) in the regulation of placental development. In this study we have examined CSF-1 production by an immortalized cell line (TCL-1) derived from the choriodecidua, transfected with a retrovirus gene coding for the large-T antigen. TCL-1 cells were uniformly positive by immunocytochemistry for the composite sub-units of human chorionic g gonadotrophin (hCG) but were negative for markers of other cell types localized at the fetal-maternal interface. Gelatinase enzymes were secreted by TCL-1 cells cultured on extracellular matrix in a manner indicative of extra-villous trophoblast. Dot-blot immunoassays and ELISA indicated that CSF-1 was secreted by TCL-1 cells, at levels comparable to primary trophoblast cells and BeWo choriocarcinoma (trophoblast tumour) cells. Reverse transcriptase-polymerase chain reaction analysis confirmed the presence in TCL-1 cells of CSF-1 receptor mRNA (c-fms gene product), indicating that the components of a potential autocrine loop were present in these cells. Proliferation of TCL-1 cells was not affected by the addition of exogenous CSF-1 but was elevated in response to treatment with a CSF-1 neutralizing antibody. The immortalized cell line, TCL-1, provides a potential model in which to investigate regulation of growth and differentiation of trophoblast cells in vitro.

Base Sequence↗
PubMed1996

Thermotaxis of human trophoblastic cells.

The objective of this study was to determine whether cultured human trophoblasts migrate in response to changes in oxygen tension or temperature. Human trophoblastic cells distributed homogenously within individual wells of standard culture plates were subjected to oxygen and thermal gradients. The redistribution of cells was determined 90 min to 18 h after these gradients had been established. Trophoblastic cells did not migrate in response to gradients of oxygen or carbon dioxide applied in this manner. In contrast, the cells migrated in response to thermal gradients of less than 1 degree C in the direction of the warmer temperature. The response began within minutes, was reversed by a change in the direction of the thermal gradient, and was inhibited at high cell concentrations. Migration was independent of proliferation or protein synthesis, but required microfilament assembly. The capacity of trophoblasts to migrate in response to small difference of temperature within the physiologic range may contribute to the initiation of placental development before contact with the maternal circulation has been established.

Arteries↗
PubMed1997

Decrease in cytochrome c oxidase activity detected cytochemically in the placental trophoblast of patients with pre-eclampsia.

This study was designed to explore the possible relationship between cytochemically detectable cytochrome c oxidase (COX) activity in the trophoblast and placental dysfunction in patients with pre-eclampsia. Fifteen placentae (10 from women with an uncomplicated pregnancy and five from patients with pre-eclampsia) were involved in this study. Localization of COX activity in the placental trophoblast was determined by ultrastructural enzyme cytochemistry using DAB as a capturing agent. COX activity was observed in the intracristal spaces and intermembrane spaces of trophoblastic mitochondria. The number of mitochondria positive for COX staining was decreased markedly in the placentae of the women with pre-eclampsia. Trophoblastic mitochondrial dysfunction may be present in placenta of patients with pre-eclampsia.

Electron Transport Complex IV↗
PubMedDate not supplied

The effect of hypoxia on human trophoblast in culture: morphology, glucose transport and metabolism.

The response to hypoxia of trophoblast isolated from term placenta and maintained in culture was studied. Trophoblast exposed to normoxic (PO2 120-130 mmHg) or hypoxic (PO2 12-14 mmHg) conditions were examined by electron microscopy. After 48 h, the cytoplasm of the hypoxic cells was more electron-dense with increased numbers of mitochondria, lysosomes and vacuoles. Compared to normoxic cells, the surface microvilli of the hypoxic cells were sparse, short and unevenly distributed. [3H]thymidine incorporation by both hypoxic and normoxic trophoblast fell rapidly and equivalently after 2 days in culture. The percentage of cells with the proliferation-associated nuclear antigen, Ki 67, also decreased, but remained higher in hypoxic cells suggesting that hypoxia retarded completion of the cell cycle (normoxia, 10.80 +/- 2.51 s.e.; hypoxia, 19.87 +/- 2.73, P < 0.01). Glucose consumption was elevated in hypoxia (3.73 +/- 1.07 s.e. mumol/10(6) cells/24 h) as compared to normoxia (1.46 +/- 0.83, P = 0.01). Although lactate production was consistently higher in hypoxia, the difference was not statistically significant (hypoxia 5.38 +/- 1.54 mumol/10(6) cells/24 h versus normoxia, 1.52 +/- 0.29, P = 0.07). After 48 h, uptake of [3H]2-deoxglucose ([3H]2DG) by hypoxic cells was reduced to 12 per cent +/- 4.3 s.e. of that in normoxic cells; return to normoxia resulted in recovery within 10 min. Lineweaver-Burk plots of [3H]2DG uptake indicated high affinity (KM 2.2 +/- 0.4 x 10(-4) M) and low affinity transporters (KM 4.5 +/- 1.6 x 10(-3) M). Northern blot analysis identified mRNA for GLUT1 and GLUT3. In hypoxia, steady-state GLUT1 and GLUT3 mRNA were approximately three- and 10-fold higher than in normoxia respectively. Inhibitors of oxidative metabolism of glucose increased the uptake of [3H]2DG within 2 h, whereas hypoxia reduced uptake. Hence, trophoblast in culture survives in extreme hypoxia, but manifests striking changes in morphology and in glucose metabolism and transport. Completion of cell cycle appears to be retarded.

Biological Transport↗
PubMedDate not supplied

p53, Bax and Bcl-2 expression, and apoptosis in gestational trophoblast of complete hydatidiform mole.

This study investigates the extent of apoptosis in complete hydatidiform mole (CHM), using an in situ 3'-end DNA labelling (TUNEL) technique on formalin-fixed and paraffin-embedded sections. The sections were also immunostained with antibodies to p53, Bax and Bcl-2 proteins. In 10 normal placenta cases and 15 CHM cases, the apoptotic index was <1 and 2-4 per cent, respectively. The labelled trophoblastic cells possessed pyknotic nuclei and densely eosinophilic cytoplasm which corresponded well to the so-called apoptotic bodies by light and electron microscopy. The p53 positive reaction was restricted to the nuclei of cytotrophoblasts and intermediate trophoblasts, while the syncytiotrophoblasts showed only rare immunolocalization. Strong p53 expression was seen most often in cytotrophoblasts of CHM (>30 per cent of nuclei) which also showed a higher apoptosis index, while cytotrophoblasts in normal placentae were weakly and focally labelled (<10 per cent of nuclei). There were statistical differences between normal and CHM cases (P<0.05). Bcl-2 accumulation, on the other hand, was observed predominantly in syncytiotrophoblasts of normal placentae, and cytotrophoblasts and intermediate trophoblasts did not express Bcl-2 in all cases. Interestingly, syncytiotrophoblasts were found to be negative for Bax protein and positive in cytotrophoblast, which is consistent with the function of the protein in conveying increased apoptosis susceptibility to this cell population. The results show that the level of apoptosis correlates with the histological type of the gestational trophoblasts, and apoptosis index is higher in cytotrophoblasts in CHM. The fact that p53 quantitative expression and an increase in the Bax/Bcl-2 ratio were also observed in CHM suggested that they may contribute partly to the high level of apoptosis.

Adult↗
PubMedDate not supplied

Viral infection of the trophoblast: time to take a serious look at its role in abnormal implantation and placentation?

Fragmentary evidence suggests that trophoblast viral infection may play a role in placental dysfunction, leading to complications including spontaneous miscarriage, preeclampsia, fetal growth restriction and preterm birth. Here, we review the mechanisms underlying differentiation and gestational age-dependent infection of trophoblast cells and the consequences of in vitro infection on trophoblast function. The relationship between trophoblast infection by common viruses and pregnancy outcomes is also analyzed. We conclude that there is sufficient evidence linking placental infection by common viruses, including viruses thought to be non-pathogenic or to have low pathogenicity, to indicate that this effect contributes to poor pregnancy outcome.

Embryo Implantation↗