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PubMed2004

Pre-eclampsia is associated with the failure of melanoma cell adhesion molecule (MCAM/CD146) expression by intermediate trophoblast.

The purpose of this study was to determine whether the expression of melanoma cell adhesion molecule (MCAM/CD146), like most other endothelial adhesion molecules, is reduced in the pregnancy disorder pre-eclampsia, and whether it is associated with the invasiveness of trophoblast. We used immunohistochemical approaches and analyzed 42 placentas from control and pre-eclamptic patients using an anti-CD146 monoclonal antibody. Our data show that in normal placentas, CD146 staining was specifically detected in intermediate trophoblasts that are most invasive and migratory, but not detected in noninvasive cytotrophoblasts or syncytiotrophoblasts. However in pre-eclampsia, CD146 was no longer present in the intermediate trophoblasts, although it was detectable in the blood vessels. At the same time, we tested CD31/PECAM-1, another endothelial adhesion molecule, and found its negative staining for all kinds of trophoblasts in both normal and pre-eclamptic placentas. The different staining patterns of CD146 in the normal and pre-eclamptic placentas provide the first evidence that in pre-eclampsia, intermediate trophoblasts fail to express CD146, implicating that CD146 plays an important role in trophoblast invasion.

Adult↗
PubMed2001

Focal adhesion kinase is a key mediator of human trophoblast development.

Trophoblast differentiation during the first trimester of pregnancy involves cell proliferation and invasion and extracellular matrix (ECM) remodeling. Reports have indicated that, in a variety of cell types, processes such as proliferation, invasion, and ECM remodeling require the turnover of focal adhesions mediated by a cytoplasmic tyrosine kinase named focal adhesion kinase (FAK). Therefore, in the present study we examined the expression and spatial localization of FAK during early human placental development. Immunocytochemical and immunoblot analysis showed that FAK and a focal adhesion-associated protein named paxillin were highly expressed between the 5th and 8th weeks of gestation, specifically in villous cytotrophoblast and extravillous trophoblast (EVT) cells. Activated FAK, phosphorylated on Tyr-397, colocalized with alpha5 integrin and matrix metalloproteinase-2 (MMP2) expression in EVT cells within a previously characterized intermediate, invasive-restrained region. FAK and paxillin expression dramatically decreased after 10 to 12 weeks of gestation coincident with increasing pO(2) levels. Exposure of human villous explants of 5 to 8 weeks to a 3% O(2) environment resulted in increased trophoblast outgrowth, cell proliferation, and detection of alpha5 integrin and MMP2, as well as increased activation of FAK in EVT cells compared with explants grown in a 20% O(2) environment. To determine whether FAK was a key requisite for trophoblast differentiation, villous explants of 5 weeks gestation were grown in Matrigel in a 3% O(2) environment and incubated with 20-mer antisense FAK oligonucleotides. A dramatic reduction of trophoblast outgrowth was observed in antisense-treated explants compared with missense and control cultures, and, in addition, cell proliferation and MMP2 activity in antisense-treated explants were dramatically reduced. These data suggest that FAK is a key kinase involved in early trophoblast cell differentiation and plays a role in regulating cell proliferation and motility during early placental development.

Antisense Elements (Genetics)↗
PubMed2002

BMP4 initiates human embryonic stem cell differentiation to trophoblast.

The excitement and controversy surrounding the potential role of human embryonic stem (ES) cells in transplantation therapy have often overshadowed their potentially more important use as a basic research tool for understanding the development and function of human tissues. Human ES cells can proliferate without a known limit and can form advanced derivatives of all three embryonic germ layers. What is less widely appreciated is that human ES cells can also form the extra-embryonic tissues that differentiate from the embryo before gastrulation. The use of human ES cells to derive early human trophoblast is particularly valuable, because it is difficult to obtain from other sources and is significantly different from mouse trophoblast. Here we show that bone morphogenetic protein 4 (BMP4), a member of the transforming growth factor-beta (TGF-beta) superfamily, induces the differentiation of human ES cells to trophoblast. DNA microarray, RT-PCR, and immunoassay analyses demonstrate that the differentiated cells express a range of trophoblast markers and secrete placental hormones. When plated at low density, the BMP4-treated cells form syncytia that express chorionic gonadotrophin (CG). These results underscore fundamental differences between human and mouse ES cells, which differentiate poorly, if at all, to trophoblast. Human ES cells thus provide a tool for studying the differentiation and function of early human trophoblast and could provide a new understanding of some of the earliest differentiation events of human postimplantation development.

Bone Morphogenetic Protein 4↗
PubMed2000

Unusual patterns of intermediate filament protein expression by the trophoblast and decidual cells of the short-tailed fruit bat, Carollia perspicillata.

In the short-tailed fruit bat (Carollia perspicillata) pregnancy can be prolonged by the occurrence of lengthy delays after implantation. This is associated with the development of highly invasive trophoblast that can penetrate the myometrium, mesenteries of the reproductive tract and the oviducts via perivascular (interstitial) routes. In order to confirm the identity and distribution of this trophoblast, intermediate filament protein immunocytochemistry was utilized. In some respects the expression of these proteins differed from what has been reported for more commonly-studied species. Cytotrophoblast in the placenta, its cytotrophoblastic shell and the highly invasive trophoblast strongly expressed cytokeratins. As pregnancy progressed, however, cytokeratin expression by syncytiotrophoblast lining much of the placental labyrinth became very weak. The cytotrophoblastic shell and highly invasive trophoblast also expressed vimentin. The highly invasive trophoblast was unusual in that it developed dendritic processes that sometimes extended out into adjacent tissues in great profusion. Decidual cells generally expressed desmin and vimentin; however, some also coexpressed cytokeratins. These observations indicate that some of the trophoblast in Carollia undergoes a significant epithelial-mesenchymal transformation. They also suggest that caution should be exercised in relying upon intermediate filament proteins as markers for cell identification purposes in exotic species, or when the patterns of protein expression by fetal and maternal cells might be altered in pathological or experimental situations.

Animals↗
PubMed2000

Does plasminogen activator inhibitor-1 (PAI-1) control trophoblast invasion? A study of fetal and maternal tissue in intrauterine, tubal and molar pregnancies.

Urokinase plasminogen activator, its receptor and the inhibitor PAI-1 are believed to control proteolysis and remodelling of maternal tissue during trophoblast invasion. This system appears to be strictly regulated in normal intrauterine pregnancies whereas tubal and molar pregnancies seem to be characterized by an uncontrolled excessive placental invasion. This study evaluates subcellular PAI-1 by immunohistochemistry in the villous placenta, in the basal plate and placental bed, and in the decidual compartments of normal, tubal and molar pregnancies. PAI-1 was present in villous syncytiotrophoblasts and co-localized focally with fibrin-type fibrinoid on the surface of the chorionic villi. Basal plate and placental bed extravillous interstitial trophoblasts, as well as vascular trophoblasts, were also PAI-1 positive. In the decidua parietalis, PAI-1 was observed in the cytoplasm of the non-invaded decidual cells. In the decidua basalis comprising the basal plate, PAI-1 was seen to be membrane-associated or confined to the extracellular matrix (ECM) facing the invasive front of anchoring villi. The ECM of decidua capsularis and chorion laeve displayed the most pronounced PAI-1 expression towards the maternal interface. In contrast, the majority of placental bed decidual cells adjacent to the interstitial and vascular trophoblasts were PAI-1 negative. Only a few stromal cells distant from the implantation site were PAI-1 positive in the tubal pregnancies and decidualization was not present. Likewise, excessive decidual necrosis and fibrinoid deposition devoid of PAI-1 was a common finding in complete molar pregnancies. These results suggest that PAI-1 defines specific extravillous invasive trophoblasts within the maternal decidua. Moreover, maternal cellular lack of PAI-1 in tubal pregnancies and excessive decidual necrosis in molar pregnancies indicate an uncontrolled placental invasion. The present data indicate that trophoblast invasion is primarily regulated by signals from decidual cells.

Chorionic Villi↗
PubMedDate not supplied

Characterization of trophoblast cell isolations by a modified flow cytometry assay.

The purity of isolated trophoblast cells is an important checkpoint in in vitro studies on the human placenta. Maintaining viability of primary cells for a prolonged period, or achieving cell proliferation in primary cell cultures, is often a matter of concern. In this paper we present a method for characterizing the purity of isolated trophoblast cells based on the expression of cytoskeletal proteins, as well as for assessing their cell cycle status, by flow cytometry. We show that after a simple permeabilization and fixation step in 70 per cent methanol, staining for cytokeratin 7 and vimentin could discriminate between trophoblast cells and contaminating populations. The method was applicable to trophoblast cells both from villous and extravillous origin. By staining the proliferation-related antigen Ki-67 and DNA, information was gained about the cell cycle status and viability of freshly isolated and cultured villous trophoblast cells. This method may help to quickly and quantitatively characterize preparations of isolated trophoblast, as well as to search for culture conditions favouring long-term survival and proliferation.

Cell Cycle↗
PubMed2001

Expression of a cytokeratin 18 neo-epitope is a specific marker for trophoblast apoptosis in human placenta.

In epithelial cells the caspase-mediated cleavage of cytokeratin 18 during apoptosis leads to the formation of a specific neo-epitope, recognized by the antibody M30. To test whether this antibody can be used as a specific marker for apoptotic trophoblast, we have stained serial sections of villi and junctional zone of first and third trimester human placenta with antibodies against cytokeratins 7 and 18, and against active caspase 3, with M30 and with the TUNEL reaction. Comparison of M30 immunoreactivities with TUNEL positivity and immunoreactivities for cytokeratins 7 and 18 clearly demonstrates that M30 specifically labels late apoptotic trophoblast cells. This finding is supported by the fact that in trophoblast, M30 immunoreactivities largely overlap with those for active caspase 3. As compared to the TUNEL test, the M30 immune reaction appears to be a highly reproducible marker for apoptotic trophoblast. This antibody stains a larger number of cells within the apoptosis cascade as compared to the TUNEL reaction, since cytokeratin 18 cleavage starts earlier than cleavage of DNA and since endonuclease activation can be bypassed in some trophoblast cells. The data suggest that M30 is superior to the TUNEL reaction as a marker for the detection of trophoblast apoptosis since it is easier to handle, more specific for apoptosis and less prone to artifacts.

Adult↗
PubMed2001

Key regulatory transcription factors involved in placental trophoblast development--a review.

Specification of the trophoblast cell lineage comprising the outermost epithelial cell layer of the blastocyst occurs early in development and is a prerequisite for implantation of the embryo and subsequent formation of the placenta, a multifunctional organ which is indispensable for the proper development of the fetus. Trophoblast stem cells of the placenta give rise to distinct highly differentiated trophoblast subtypes which build the functional units of the organ. These specialized cells assure anchorage of the embryo to the mother, establishing a vascular connection transporting nutrients and gases and expression of hormones that are required for the successful progression of pregnancy. Developmental processes of the trophoblast occur in a spatially and temporally highly organized manner. Despite these facts, little is known on the key regulatory factors which commit and differentiate trophoblast cells in humans. Recent studies in mice, however, provided evidence that various cell-type specific transcription factors play crucial roles in the developmental programme of the trophoblast. In this review we will focus on the function of these major regulatory factors in murine trophoblast/placental development and discuss the potential role of their homologues in the human system.

Adult↗
PubMed2001

Villous trophoblast: morphometric perspectives on growth, differentiation, turnover and deposition of fibrin-type fibrinoid during gestation.

Villous trophoblast growth and deposition of perivillous fibrin-type fibrinoid were examined in human placentas from 10-41 weeks of gestation. The main aims were: (1) to study growth of different trophoblast domains implicated in epithelial turnover (proliferation, differentiation, extrusion, denudation); (2) to test predictions about relationships between fibrinoid deposits and intervillous volume or villous surface area; and (3) to derive baseline data for future studies on complicated pregnancies. Microscopical fields on trichrome-stained paraffin sections were selected by systematic random sampling. Volumes were estimated stereologically by point counting and surface areas by intersection counting. Apparent differences were tested by analyses of variance and relationships by regression and contingency table analyses. All compartments increased in absolute volume and/or surface area although not at the same rates. Relative volumes of cytotrophoblast were greater at earlier stages (10-20 weeks) but, due to differential growth, syncytiotrophoblast nuclear aggregation sites (syncytial knots and 'bridges') occupied greater proportions of trophoblast volume and surface near term (37-41 weeks). Fibrinoid volume correlated positively with intervillous volume and villous surface area but, relative to intervillous volume, seemed to increase near term. Findings confirm that the incidence of syncytial knots increases during gestation and contributes to trophoblast thickness variability. Greater relative volumes and surfaces of syncytial 'bridges' are consistent with increased incidences of true intervillous bridges and/or villous branching points. These findings support the notion that fibrinoid deposition during normal gestation is influenced by the quality of vascular perfusion but also emphasize that the villous surface is another important factor. Haemostatic events operate at the maternal surface of trophoblastic epithelium and influence the steady state between coagulation and fibrinolysis. Fibrinoid is deposited at sites of trophoblast de-epithelialization and these arise following trauma (e.g. abruption of intervillous bridges) or during the extrusion phase of normal epithelial turnover. Like knots and bridges, sites of de-epithelialization also expand at a faster rate than overall villous surface area. These and other events in villous development can be interpreted in terms of a coherent concept of epithelial turnover in which proliferation early in gestation is mainly for growth whilst that at later stages is mainly for renewal and repair.

Cell Differentiation↗
PubMedDate not supplied

Extravillus endovascular implantation site trophoblast invasion is abnormal in complete versus partial molar pregnancies.

This study examines endovascular trophoblast invasion in pregnancies complicated by complete hydatidiform mole (CM), partial hydatidiform mole (PM) and non-molar abortions (HA). Two hundred consecutive cases from a supra-regional referral centre for suspected trophoblastic disease were examined histologically with particular regard to the presence or absence of endovascular trophoblast invasion of decidual vessels. There were 57 CM, 75 PM and 68 HA. The prevalence of normal endovascular invasion of decidual vessels was significantly lower in CM compared to all other clinical groups, amongst which there were no significant differences. Endovascular trophoblast was identified in about 80 per cent of HA and PM moles, compared to only around 25 per cent of CM (Z = -4.0, P< 0.0001). The majority of cases of complete mole demonstrated a similar appearance, of implantation site showing florid interstitial extravascular trophoblast invasion with surrounding of decidual vessels but without normal endovascular trophoblast invasion or 'plugging' seen. In many cases, there also appeared to be destruction of decidual vessels with interstitial haemorrhage and extensive fresh blood clot present in the histological sections. These findings may provide some explanation regarding the mechanism of clinical findings in molar pregnancy.

Decidua↗
PubMedDate not supplied

Hypobaric hypoxia and villous trophoblast: evidence that human pregnancy at high altitude (3600 m) perturbs epithelial turnover and coagulation-fibrinolysis in the intervillous space.

Spatial relationships between fibrin-type fibrinoid and regions of villous trophoblast were examined in order to address two main questions: [1] is high-altitude pregnancy accompanied by changes in the sizes of trophoblast compartments (cytotrophoblast, syncytiotrophoblast, denudation sites)?, and [2] do highland placentae differ in the amounts and distribution patterns of perivillous fibrin-type fibrinoid? Placentae were collected from two ethnic groups completing term pregnancies at low (400 m above sea level; n=25) and high (3600 m; n=45) altitude in Bolivia. Masson trichrome-stained sections were sampled randomly and analysed stereologically to estimate compartment volumes and surfaces. Comparisons were drawn using variance, Chi-squared and contingency table analyses. At high altitude, birthweights were 265 g lower and placentas had a larger intervillous space (270 cf 181 cm(3)), less fibrin-type fibrinoid (4.1 cf 8.4 cm(3) by volume; 2570 cf 4430 cm(2) by surface area), less villous trophoblast (50 cf 73 cm(3)) and a smaller villous surface (5.6 cf 7.0 m(2)). Volumes were reduced in all syncytiotrophoblast compartments (with and without nuclear aggregations). Cytotrophoblast was maintained and its relative volume increased significantly (from 2.7 to 3.6 per cent of trophoblast volume). Decreases in villous surface area affected primarily thinner (nuclear aggregate-free) regions of syncytium. Regardless of altitude, fibrin-type fibrinoid was deposited non-randomly: it was preferentially located at sites of trophoblast denudation. Although no altitudinal differences in fibrin-type fibrinoid patterns were detected, absolute surfaces were diminished on denuded and thinner regions of trophoblast but not on syncytial knots or bridges. Ethnic differences at low altitude (relatively greater deposits on denudations in Amerindians) were minimized at high altitude. We conclude that pregnancy at high altitude alters the epithelial steady state (towards cytotrophoblast and away from syncytiotrophoblast) and the coagulation-fibrinolysis steady state in the intervillous space (to favour fibrinolysis over coagulation). Thinner regions of syncytiotrophoblast may be the main sites of greater fibrinolytic or anticoagulatory activity. The findings are partly consistent with results from in vitro studies which indicate that hypoxia stimulates proliferation of cytotrophoblast but impairs fusion into syncytium.

Adult↗
PubMed2002

Apoptotic activity in villous trophoblast cells during B19 infection correlates with clinical outcome: assessment by the caspase-related M30 Cytodeath antibody.

Human parvovirus B19 (B19) infection during pregnancy can result in horizontal transmission of the virus and congenital infection. The main targets for B19 replication are the erythroid precursor cell of the colony and burst forming units. The cellular receptor necessary for B19 infectivity is globoside. Other non-erythroid cells can express this receptor, including megakaryocytes, endothelial cells, cardiac myocytes and placental trophoblast cells. B19 infection of globoside-containing erythroid cells results in cell death via apoptosis. We asked whether globoside-containing placental trophoblast cells, although not permissive for complete viral replication, would show evidence of apoptotic activity as a result of B19 infection. Placentas from 26 pregnancies with documented maternal and/or congenital B19 infection, 14 with poor outcomes and 12 with good outcomes were examined for evidence of apoptosis using the caspase-related M30 Cytodeath monoclonal antibody (Mab). M30 Mab recognizes a caspase 3 directed cleavage event within cytokeratin 18, a protein widely distributed in epithelial cells, of which trophoblast cells are classified. The results of the immunohistochemical analysis revealed a significant number of M30-staining placental villous trophoblast cells from B19-complicated pregnancies with poor outcomes compared to B19-complicated pregnancies with good outcomes or the 24 age-matched controls (P< 0.001). This is the first description of an association between B19-complicated pregnancies ending in foetal death and increased apoptosis within placental villous trophoblast cells. Damage due to premature death of the protective barrier of the placental trophoblast layer may compromise its integrity and play a role in pathogenesis.

Antibodies, Monoclonal↗
PubMed2003

Fibrin-type fibrinoid in placentae from pregnancies associated with maternal smoking: association with villous trophoblast and impact on intervillous porosity.

Smoking during pregnancy perturbs maternal haemostasis via activated coagulation which could include greater coagulation (fibrin-type fibrinoid deposition) in the placental intervillous space. This might affect intervillous haemodynamics and transport of oxygen and nutrients to the fetus. Fibrin deposits could influence the sizes and numbers of intervillous spaces ('pores') and perivillous fibrin could reflect changes in the nature or activity of trophoblast. Here, we test whether or not smoking is associated with differences in the composition of villous trophoblast, the amounts and patterns of fibrin and, hence, the dimensions and numbers of intervillous pores. Random samples of placentae were taken from pregnancies classified according to smoking status (non-smokers, light smokers, heavy smokers). Stereology was used to estimate volumes of intervillous space and fibrin, test for differences in trophoblast composition and patterns of fibrin deposition at the villous surface, and determine the impact of deposits on the mean volumes and theoretical numbers of intervillous pores. No group differences were found in total volumes or surfaces of trophoblast or total volume of intervillous fibrin. However, the total surfaces of syncytial knots declined in smokers and the surfaces of syncytial bridges increased. Particularly in heavy smokers, this was associated with reduced deposits of perivillous fibrin at syncytial knots. In all placentae, the greatest deposits occurred where there was trophoblast denudation. Little fibrin was seen on thin regions of syncytium. Regardless of smoking status, intervillous fibrin reduced intervillous pore size and increased pore number. However, heavy smokers had larger pores. Reductions in syncytial knots are consistent with reports that smoking reduces the incidence of trophoblast apoptosis whilst increases in syncytial bridges are consistent with enhanced branching angiogenesis. Results confirm that perivillous fibrin accumulates preferentially at denudation sites. They also suggest that smoking perturbs the normal pattern of fibrin deposition, that the impact is greater in heavy smokers and that the placental site is privileged or active in terms of fibrinolytic or anti-coagulatory activity. This activity seems to reside in thin regions of syncytium.

Adult↗
PubMed2000

Trophoblast-uterine interactions in the first days of implantation: models for the study of implantation events in the human.

The most profound changes in the relationship of the trophoblast to endometrial tissues occur in the first 5 days after the initiation of implantation. Not only have the earliest stages--adhesion and epithelial penetration--never been seen in the human, but also the trophoblastic plate and lacunar stages that follow are not available for modern investigative methods. Studies of appropriately timed endometrium and of trophoblast- and endometrium-derived cell lines have important implications for aspects of implantation. Use of nonhuman primates and other animal models for appropriate stages in implantation could further our understanding of direct trophoblast-uterine interactions. The mechanisms involved in epithelial penetration by infiltration of the syncytial trophoblast into the uterine luminal epithelium could be studied profitably using the marmoset or the ferret. Drawing of the blastocyst into an interstitial location might be investigated in the guinea pig. Formation of trophoblastic lacunae can be investigated in the cynomolgus monkey. By using such animal models of events of implantation in situ, implications concerning the molecules involved in adhesion, penetration of junctional complexes, and uterine vessel invasion that have been derived from in vitro or murine studies may be placed in context.

Animals↗
PubMed2003

Persistent low levels of human chorionic gonadotropin: A premalignant gestational trophoblastic disease.

OBJECTIVE: This study was undertaken to evaluate the significance of persistent low-level human chorionic gonadotropin (hCG) titers (usually <50 IU/L) in the absence of clinical evidence of pregnancy or gestational trophoblastic disease. STUDY DESIGN: The USA hCG Reference Service consulted on 114 cases with persistent low levels of hCG; 51 had false-positive hCG results. The remaining 63 cases had real hCG results and are presented here. RESULTS: Antecedent gestational events included hydatidiform mole (27), pregnancy (35), and gestational trophoblastic neoplasm (1). Forty of the 63 (64%) cases received therapy, including chemotherapy (38), hysterectomy (2), or both (10). Despite treatment, in all cases, low hCG titers persisted. After 1 to 4.5 years of low titers, four women had a sudden rapid increase in hCG levels, and malignant disease was confirmed or clearly suggested (gestational trophoblastic neoplasm [3] and placental site trophoblastic tumor [1]). Invasive trophoblast antigen (ITA) is a marker of invasive cytotrophoblast cells. ITA was measured in 38 of the cases with persistent low hCG, in all cases ITA accounted for less than 25% of the hCG concentration. It was also determined in the 4 cases indicated with malignant disease, accounting for more than 80% of the hCG. CONCLUSION: The presence of persistent low-level hCG titers defines a subset of women with preinvasive or quiescent gestational trophoblastic disease. ITA effectively detected the presence or absence of invasive cells in these cases. The recommended management of the quiescent disease is close surveillance without therapy until malignant disease detected.

Chorionic Gonadotropin↗
PubMed2003

Trophoblast expression of fms-like tyrosine kinase 1 is not required for the establishment of the maternal-fetal interface in the mouse placenta.

Fms-like tyrosine kinase 1 (Flt1)/vascular endothelial growth factor (VEGF) receptor 1, a receptor for VEGF-A and placental growth factor, is expressed in the spongiotrophoblast layer that segregates the maternal and fetal vasculature in the mouse placenta. A soluble form of Flt1 (sFlt1) produced in the mouse and human placenta can also be detected in the maternal blood. Levels of maternal sFlt1 are elevated in preeclampsia, suggesting that placental sFlt1 plays roles in regulating the maternal vasculature during pregnancy. However, it remains to be determined whether placental Flt1/sFlt1 serves as a regulator of VEGF-A activity in the placenta per se. Here, we investigated the placental development in Flt1-deficient mice. Flt1 is expressed in a subpopulation of ectoplacental cone cells and later marks the spongiotrophoblast cells, peri/endovascular trophoblast cells, and trophoblast glycogen cells. The labyrinth of Flt1lacZ/lacZ placentae lacked the fetal capillary network because of a defect in allantoic mesoderm invasion. To address whether the absence of Flt1 in the trophoblast alone affects placental development, we investigated chimeric placentae comprised of Flt1lacZ/lacZ trophoblast and Flt1+/+ mesoderm, generated by tetraploid aggregation. Fetal growth was supported normally, and no defect in the formation of placental circulation into the maternal spiral artery or invasion of peri/endovascular trophoblast was detected. These findings indicate that trophoblast-derived Flt1/sFlt1 is dispensable for the initial establishment of the maternal-fetal interface in the mouse placenta. Targeting maternal sFlt1 levels for treatment of preeclampsia may thus be possible without affecting the proper formation of the placenta.

Animals↗
PubMed1993

Recombinant entactin promotes mouse primary trophoblast cell adhesion and migration through the Arg-Gly-Asp (RGD) recognition sequence.

In vitro culture of mouse blastocysts during the period coinciding with implantation has revealed that primary trophoblast cells can adhere and migrate in serum-free medium when provided with certain extracellular matrix components, including fibronectin and laminin. Tightly associated with laminin is the glycoprotein, entactin, that may play an important role in basement membrane assembly and cell attachment. Mouse blastocysts were studied using this in vitro model to determine whether entactin was capable of mediating trophoblast invasive activity. Although entactin has never been shown to promote cell migration, we report here that recombinant entactin supported blastocyst outgrowth in a dose-dependent manner, with a maximal effect at 20-50 micrograms/ml. The ability of trophoblast cells to adhere and migrate on entactin was specifically inhibited by anti-entactin antibody, but not by antibodies raised against laminin. The synthetic peptide, Gly-Arg-Gly-Asp-Ser-Pro, that contains the Arg-Gly-Asp (RGD) integrin recognition site, reversibly inhibited entactin-mediated blastocyst outgrowth in a dose-dependent manner, but had no effect on laminin-mediated outgrowth. The synthetic peptide, Gly-Phe-Arg-Gly-Asp-Gly-Gln, that comprises the actual RGD-containing sequence within entactin, promoted trophoblast outgrowth when immobilized on the substratum. Furthermore, a mutated recombinant entactin, altered to contain a Glu in place of Asp at the RGD site, provided no trophoblast cell adhesive activity. We conclude that entactin promotes trophoblast outgrowth through a mechanism mediated by the RGD recognition site, and that it may play an important role during invasion of the endometrial basement membrane at implantation.

Amino Acid Sequence↗
PubMed1972

Further evidence concerning the autoantigenic status of the trophoblast.

Heterologous antisera were raised by inoculation of rabbits with fairly pure suspensions of trophoblast, lymphoid, fetal (excluding placental components), epidermal, decidual, and renal cells from Fischer rats. After absorption of hemagglutinins, these antisera were assayed for abortifacient activity by intramuscular inoculation into time-mated Fischer females. The anti-trophoblast serum aborted all the recipients, but had some nonspecific activity in that it caused the deaths of 12% of them. Anti-lymphocyte serum was more toxic and less potent as an abortifacient. None of the other sera harmed either the mothers or their fetuses. However, the anti-kidney cell serum caused kidney lesions. Absorption of the anti-trophoblast serum with lymphoid cells completely removed its toxicity for the pregnant females without perceptible impairment of its abortifacient activity. However, the latter could be removed by absorption with trophoblast cells. (a) The lymphocyte-absorbed anti-trophoblast serum was equally effective in aborting rats over the range 7-18 days postconception; (b) a single injection of 1 ml was sufficient in most cases, and (c) it was equally efficacious in terminating gestation in rats irrespective of their genetic constitution, and (d) its effect was highly species-specific. These findings support the premise that a unique antigen (or antigens), of possible clinical significance, is associated with trophoblast cells.

Abortion, Induced↗