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PubMed1995

Neural transplantation of the rat midgestation trophoblast.

The trophoblast may serve as an example of tissue that is endowed with invasive properties under physiological conditions. Invasiveness of the trophoblast is enabled by the secretion of various proteases capable of degrading extracellular matrix components. Trophoblast invasive behavior is strictly controlled by anti-invasive factors produced by uterine decidual cells. To assess invasive abilities of trophoblast cells we have transplanted E9 and E14 rat trophoblast (i.e. the trophoblast obtained on embryonic day 9 and 14) into the brain of adult rats. The brain parenchyma as an immunologically privileged site is suitable for acceptance of grafts of different tissues. Moreover, the trophoblast placed into the CNS lacks inhibitory influence of anti-invasive factors that normally regulate trophoblast invasivity in the course of intrauterine gestation. To visualize migration of grafted cells the nuclei of the trophoblast were labelled with bromodeoxyuridine prior to neural grafting. The transplant of E9 and E14 trophoblast cells obtained a blood nourishment from host vessels. A proper vascularization is necessary for a further transplant growth. The transplant contained labyrinthine trophoblast cells and giant cells that are typical for the rat placenta. Vital trophoblast cells were found in all grafts whose age did not exceed a lifespan of normal rat trophoblast cells i.e. 21-22 days. In the centre of the graft, no blood vessels were observed. Interstitial spaces of neighbouring trophoblast cells were filled with the host blood and morphology of these spaces mimicked lacunae of the placental trophoblast. E9 and E14 rat trophoblast continued to differentiate after transplantation into the CNS of adult rats. Histological structure of the grafts were compared with microscopical morphology of the normal rat placenta. E9 and E14 trophoblast is considerably differentiated and it does not invade a neighbouring tissue. Trophoblast cells located at t the graft periphery may migrate on free surfaces but they do not invade through the host parenchyma. Migration occurs at a limited distance from the transplant and the cells remain in a close contact with other trophoblast cells in the graft via their cytoplasmatic processes. The ability to lyse host blood vessels and form vascular lacunae is well preserved in E9 and E14 trophoblast after grafting into the CNS. This ability is necessary for a proper transport of nutrients from the host blood stream to fetal tissue that normally occurs in the placenta.

Animals↗
PubMed2005

Modulation of trophoblast stem cell and giant cell phenotypes: analyses using the Rcho-1 cell model.

Trophoblast giant cells are located at the maternal-embryonic interface and have fundamental roles in the invasive and endocrine phenotypes of the rodent placenta. In this report, we describe the experimental modulation of trophoblast stem cell and trophoblast giant cell phenotypes using the Rcho-1 trophoblast cell model. Rcho-1 trophoblast cells can be manipulated to proliferate or differentiate into trophoblast giant cells. Differentiated Rcho-1 trophoblast cells are invasive and possess an endocrine phenotype, including the production of members of the prolactin (PRL) family. Dimethyl sulfoxide (DMSO), a known differentiation-inducing agent, was found to possess profound effects on the in vitro development of trophoblast cells. Exposure to DMSO, at non-toxic concentrations, inhibited trophoblast giant cell differentiation in a dose-dependent manner. These concentrations of DMSO did not significantly affect trophoblast cell proliferation or survival. Trophoblast cells exposed to DMSO exhibited an altered morphology; they were clustered in tightly packed colonies. Trophoblast giant cell formation was disrupted, as was the expression of members of the PRL gene family. The effects of DMSO were reversible. Removal of DMSO resulted in the formation of trophoblast giant cells and expression of the PRL gene family. The phenotype of the DMSO-treated cells was further determined by examining the expression of a battery of genes characteristic of trophoblast stem cells and differentiated trophoblast cell lineages. DMSO treatment had a striking stimulatory effect on eomesodermin expression and a reciprocal inhibitory effect on Hand1 expression. In summary, DMSO reversibly inhibits trophoblast differentiation and induces a quiescent state, which mimics some but not all aspects of the trophoblast stem cell phenotype.

Animals↗
PubMed2004

Expression and importance of matrix metalloproteinase 2 and 9 (MMP-2 and -9) in human trophoblast invasion.

BACKGROUND: The aim of this study was to examine the invasiveness of first trimester trophoblasts according to the secretion profile of MMP-2 and -9 at different gestational stages, and to test the similarity between primary trophoblast cell-culture and the JAR choriocarcinoma cell-line. METHODS: First trimester trophoblasts were divided into two groups: 6-8 weeks (early) and 9-12 w (late) of gestation. The two trophoblast groups and JAR cells were cultured in medium, with various concentrations of forskolin and Epidermal Growth Factor (EGF). Proteolytic activity was detected by zymography and invasiveness was assessed by Matrigel invasion assay. Student's T-test was used for statistical analysis. RESULTS: In 6-8 w trophoblast, proMMP-2 was only slightly dominant over proMMP-9 (53.2% vs. 46.8% respectively), whereas in 9-12 w, proMMP-9 was clearly dominant over proMMP-2 (61.7% vs.38.3% respectively). In JAR cells proMMP-2 was strongly dominant (90.2% vs.9.8% respectively). In JAR cells forskolin significantly increased proMMP-2 and -9 secretion (128.5% +/- 12 and 183.2% +/- 27.9 of control, respectively). EGF had a dual effect on JAR cells: at 8 ng/ml both proMMP-2 and -9 were increased (133.5% +/-15 and 223.9% +/- 32.4 of control, respectively) while at 80 ng/ml both proMMP-2 and -9 were decreased (65.1% +/- 18.3 and 66.6% +/- 37 of control, respectively). Forskolin significantly increased both proMMP-2 and -9 secretion in 6-8 w and 9-12 w trophoblasts (125.9% +/- 6.3,128.4% +/- 6.4; 169.7% +/- 20.3, 120.3% +/- 4.5 of control, respectively). EGF also significantly increased both proMMP-2 and -9 secretion in 6-8 w and 9-12 w trophoblasts (141.22% +/- 14.8, 138.8% +/- 10.3; 168.3% +/- 18.2, 117.3 +/- 3.8 of control, respectively). Both forskolin and EGF increased trophoblast cells invasiveness in all groups. The invasive ability of trophoblast cells, induced by forskolin, was reduced by MMP-2 antibody in: JAR cells, 6-8 w and 9-12 w trophoblasts. Likewise trophoblast invasion induced by EGF was reduced by MMP-2 antibody in all groups. However the invasive ability induced by forskolin or EGF was inhibited by MMP-9 antibody only in trophoblasts from 9-12 w. CONCLUSIONS: First trimester trophoblasts express differential gelatinase secretion profile according to the gestational week. In JAR and early trophoblasts (6-8 w) MMP-2 is the main gelatinase and the key enzyme in trophoblast invasion. Thereafter in late first trimester trophoblasts (9-12 w), both MMP-2 and -9 participate in trophoblast invasion.

Cell Line, Tumor↗
PubMed2003

Gestation stage-dependent intrauterine trophoblast cell invasion in the rat and mouse: novel endocrine phenotype and regulation.

Trophoblast cell invasion into the uterine wall is characteristic of hemochorial placentation. In this report, we examine trophoblast cell invasion in the rat and mouse, the endocrine phenotype of invasive trophoblast cells, and aspects of the regulation of trophoblast cell invasion. In the rat, trophoblast cells exhibit extensive interstitial and endovascular invasion. Trophoblast cells penetrate through the decidua and well into the metrial gland, where they form intimate associations with the vasculature. Trophoblast cell invasion in the mouse is primarily interstitial and is restricted to the mesometrial decidua. Both interstitial and endovascular rat trophoblast cells synthesize a unique set of prolactin (PRL)-like hormones/cytokines, PRL-like protein-A (PLP-A), PLP-L, and PLP-M. Invading mouse trophoblast cells also possess endocrine activities, including the expression of PLP-M and PLP-N. The trafficking of natural killer (NK) cells and trophoblast cells within the mesometrial uterus is reciprocal in both the rat and mouse. As NK cells disappear from the mesometrial compartment, a subpopulation of trophoblast cells exit the chorioallantoic placenta and enter the decidua. Furthermore, the onset of interstitial trophoblast cell invasion is accelerated in mice with a genetic deficiency of NK cells, Tg epsilon 26 mice, implicating a possible regulatory role of NK cells in trophoblast cell invasion. Additionally, the NK cell product, interferon-gamma (IFNgamma), inhibits trophoblast cell outgrowth, and trophoblast cell invasion is accelerated in mice with a genetic deficiency in the IFNgamma or the IFNgamma receptor. In summary, trophoblast cells invade the uterine wall during the last week of gestation in the rat and mouse and possess a unique endocrine phenotype, and factors present in the uterine mesometrial compartment modulate their invasive behavior.

Animals↗
PubMed2004

Regulation of trophoblast beta1-integrin expression by contact with endothelial cells.

BACKGROUND: In human and non-human primates, migratory trophoblasts penetrate the uterine epithelium, invade uterine matrix, and enter the uterine vasculature. Invasive trophoblasts show increased expression of beta1 integrin. Since trophoblast migration within the uterine vasculature involves trophoblast attachment to endothelial cells lining the vessel walls, this raises the possibility that cell-cell contact and/or factors released by endothelial cells could regulate trophoblast integrin expression. To test this, we used an in vitro system consisting of early gestation macaque trophoblasts co-cultured on top of uterine microvascular endothelial cells. RESULTS: When cultured alone, trophoblasts expressed low levels of beta1 integrin as determined by quantitative immunofluorescence microscopy. When trophoblasts were cultured on top of endothelial cells for 24 h, the expression of trophoblast beta1 integrin was significantly increased as determined by image analysis. beta1 Integrin expression was not increased when trophoblasts were cultured with endothelial cell-conditioned medium, suggesting that upregulation requires direct contact between trophoblasts and endothelial cells. To identify endothelial cell surface molecules responsible for induction of trophoblast integrin expression, trophoblasts were cultured in dishes coated with recombinant platelet endothelial cell adhesion molecule-1 (PECAM-1), intercellular adhesion molecule-1 (ICAM-1), or alphaVbeta3 integrin. Trophoblast beta1 integrin expression (assessed by immunofluorescence microscopy and Western blotting) was increased when PECAM-1 or alphaVbeta3 integrin, but not ICAM-1, was used as substrate. CONCLUSIONS: Direct contact between trophoblasts and endothelial cells increases the expression of trophoblast beta1 integrin.

Journal Article↗
PubMed1997

Functional analysis of trophoblast giant cells in parthenogenetic mouse embryos.

Diploid mouse embryos containing only maternal DNA (parthenotes) fail, in part, because the inner cell mass does not induce the trophoblast to grow. In this study, we asked whether any of the defects in parthenotes may arise from alterations in trophoblast function. We examined the expression of genes important for normal trophoblast function and found several trophoblast genes that were expressed at normal levels in the primary trophoblast cells of parthenotes: E-cadherin, a cell adhesion molecule, was expressed normally in both the ICM and trophectoderm of parthenogenetic blastocysts and blastocyst outgrowths; the gene for Hxt, a basic helix-loop-helix factor that regulates trophoblast development, was expressed in both zygotic and parthenogenetic giant cells; placental lactogen-1, a hormone that is normally secreted by trophoblast giant cells, was expressed in most of both parthenogenetic and normal trophoblast cells; and the 92 kDa matrix metalloproteinase, gelatinase B, also known as MMP-9, was secreted at equivalent levels by both zygotic and parthenogenetic blastocyst outgrowths. However, once the outgrowths had developed, a subpopulation of trophoblast cells in parthenogenetic embryos had decreased DNA replication and significantly fewer nucleoli per nucleus than did zygotic embryos. Moreover, the parthenogenetic trophoblast cells growing out from blastocysts had a decreased viability in culture. These data suggest that, although parthenogenetic embryos are able to initiate primary trophoblast differentiation, the stability and continued differentiation of trophoblast giant cells may be abnormal. Our data support the hypothesis that the deficiency of secondary trophoblast giant cells may contribute to the decline of parthenogenetic embryos and suggest that the factors controlling this subset of trophoblast are distinct from those for primary trophoblast.

Animals↗
PubMed1978

Factors affecting trophoblast growth in extrauterine sites.

The effect of genetical dissimilarity between the trophoblast and host on trophoblast growth was studied in extrauterine sites, where people can observe trophoblast growth without the complicating factors of the uterine environment. Trophoblast growth was estimated in this study by measuring the extent of trophoblast proliferation in the kidney and testis per body weight in the testis. The results showed that the trophoblast growth was not enhanced by genetical dissimilarity, but was probably determined by the capacity of the host to support trophoblast growth and the capacity of the trophoblast itself to grow. No hormonal influence on trophoblast growth was observed. When hosts were immunized with double skin grafts from donors, however, the success rate of attempted transplantation of the blastocyst was remarkably lowered and trophoblast growth was also suppressed in terms of the number of trophoblast cells and the extent of trophoblast proliferation. In such cases, intensive lymphocytic infiltration was seen between the trophoblast and host tissues. This suggests that some antigenicity on the trophoblast may be expressed in vivo under some conditions, e.g., in the strongly immunized host by the donor's antigen and the immunity to this antigen suppresses trophobalst growth.

Animals↗
PubMed1994

Production of interferons in human placental trophoblast subpopulations and their possible roles in pregnancy.

The human cytotrophoblasts are the first fetal cells to arise during embryogenesis and are the progenitor cells to villous (noninvasive), syncytiotrophoblast (noninvasive), "intermediate" extravillous (invasive), and "anchoring" extravillous (invasive) trophoblast subpopulations. These trophoblast subpopulations were isolated from first- and third-trimester placentae and were stimulated with Sendai virus, granulocyte-macrophage colony-stimulating factors (GM-CSF), and platelet-derived growth factor (PDGF) to produce interferons (IFNs). GM-CSF and PDGF induced very low levels of IFN in first-trimester extravillous and villous trophoblast subpopulations. Highly proliferating and invasive intermediate extravillous trophoblast cultures produced five- to eightfold more IFNs than villous trophoblast cultures and two- to fivefold more IFN than the syncytiotrophoblast cultures when stimulated with Sendai virus. Syncytiotrophoblast cultures produced higher levels of IFNs (up to twofold) than villous trophoblast cultures when stimulated with the same virus. Pretreatment of first-trimester extravillous and villous trophoblast cultures with GM-CSF and PDGF followed by infection with Sendai virus resulted in greater IFN production than when the cultures were stimulated with virus alone. The levels of IFN produced were dependent on the type of trophoblast, the type of inducer, and the stage of differentiation of the trophoblasts. The purified trophoblast IFNs have potent antiviral activities when assayed on human amniotic WISH cells, and they inhibited proliferation of normal trophoblasts and trophoblast-derived malignant cells in vitro without any toxicity. Furthermore, the trophoblast IFNs activated NK cell activity and suppressed mitogen-stimulated lymphocyte proliferation at concentrations of between 10 and 1,000 IU/ml. The possible functions of the trophoblast IFNs during pregnancy are discussed with respect to human placental and fetal protection and development.

Cell Division↗
PubMed1989

Glucose utilization by enzymatically-formed trophoblastic vesicles and Day-14 porcine blastocysts.

The total glucose metabolism of 48-h spherical trophoblastic vesicles, Day-60 trophoblastic vesicles sections and Day-14 porcine blastocyst sections was measured by the method of O'Fallon and Wright (1). Trophoblastic vesicles were formed by enzyme dispersal in Day-14 porcine blastocysts. Glucose was based on DNA content of the tissue measured by diamino benzoic acid reaction with DNA (2). Slope of the lines (PMoles glucose utilized/4 h x DNA content) was different between Day-14 blastocyst sections and 48 h trophoblastic vesicles (P </= 0.062) and between Day-14 blastocyst sections and Day-60 trophoblastic vesicles sections (P >/= 0.05). Slopes of the lines were identical between 48-h trophoblastic vesicles and Day-60 trophoblastic vesicles sections (P >/= 0.87). Average glucose utilization on a per ng DNA basis was calculated. Day-14 blastocyst sections utilized 0.67 Pmoles glucose/4 h per ng DNA, Day-60 trophoblastic vesicles sections; 0.57; and 48-h sperical trophoblastic vesicles used 0.29. It is hypothesized that the change in glucose utilization between the Day-14 porcine blastocyst and enzymatically formed trophoblastic vesicles may be due to a decrease in metabolism as a consequence of in vitro culture. Further, it is theorized that Day-60 trophoblastic vesicles sections used higher quantities of glucose than 48-h sperical trophoblastic vesicles on a per ng DNA basis due to the increased availability of glucose to the cells of the inner layers, caused by the sectioning of the tissue. The results of this study identify changes in glucose metabolism of enzymatically formed porcine trophoblastic vesicles during culture. It is proposed that enzymatically-formed trophoblastic vesicles be used as a model system for the study of embyro metabolism.

Journal Article↗
PubMed1996

Expression of melanoma cell adhesion molecule in intermediate trophoblast.

Melanoma cell adhesion molecule (Mel-CAM), also known as MUC18, is a cell adhesion molecule belonging to the immunoglobulin supergene family. Because of the importance of cell adhesion molecules in trophoblastic function and development, we studied the immunohistochemical distribution of Mel-CAM in trophoblastic cells in the implantation site and the normal placenta and compared it with a variety of gestational trophoblastic lesions. Formalin-fixed paraffin-embedded tissues from 44 normal placentas, 54 implantation sites (37 normal and 17 exaggerated), 13 hydatidiform moles, 13 placental site trophoblastic tumors (PSTT), and 16 choriocarcinomas were evaluated for Mel-CAM expression in trophoblast using a Mel-CAM-specific polyclonal antibody and an immunoperoxidase method. Mel-CAM was demonstrated in intermediate trophoblastic (IT) cells in all normal placentas, implantation sites, and exaggerated placental sites. Mel-CAM staining was also found in all the multinucleated IT cells in the placental site. In contrast, Mel-CAM was not detected in either cytotrophoblast (CT) or syncytiotrophoblast (ST). Similarly, in hydatidiform moles, Mel-CAM was confined to IT. In trophoblastic neoplasms, Mel-CAM was expressed in all 13 placental site trophoblastic tumors, and in 14 of 16 (88%) choriocarcinomas. Mel-CAM staining was localized to IT in both placental site trophoblastic tumors and in choriocarcinomas. In conclusion, Mel-CAM is a specific and sensitive marker for IT differentiation in normal placentas, implantation sites, and in gestational trophoblastic lesions. The differential staining pattern of Mel-CAM provides support for a dual pathway of trophoblastic differentiation in the normal placenta and in gestational trophoblastic lesions in which CT differentiates directly into ST on the villous surface, compared with the differentiation of CT to IT and then into multinucleated IT cells in extravillous sites. In view of the difficulty in distinguishing IT from CT by conventional light microscopy, it is proposed that IT cells be defined on the basis of both their morphologic features and immunophenotype as a mononucleate trophoblastic cell that expresses Mel-CAM.

Antigens, CD↗
PubMed1997

Trophoblastic lesions of the placental site.

The trophoblast of the chorionic villi as well as the hydatidiform mole and choriocarcinoma have been recognized and studied for many years. However, the trophoblast comprising the implantation site, chorionic plate, chorion laeve, cell islands and septa have only in recent years received attention in the literature. These "extravillous" trophoblastic cells were originally referred to as "X" cells due to doubt regarding their derivation from either maternal or fetal tissue (70). Subsequent studies determined that they were trophoblastic in origin (42), but the term X-cell is still in use today by some researchers (30, 4). Due to continued uncertainty regarding their nature and origin, many other terms have been used including syncytial wandering cells (21), placental site trophoblast, placental site giant cells (42), extravillous trophoblast (25), extravillous cytotrophoblast, nonvillous trophoblast, and intermediate trophoblast (49). Light microscopic and immunohistochemical studies have led to elucidation of specific morphologic and biochemical features of the extravillous trophoblast (48-50) which is commonly designated as the "intermediate trophoblast". Lesions of the "intermediate" or extravillous trophoblast of the placental site include the exaggerated placental site, the placental site trophoblast tumor and the recently described placental site nodule. This article will review the clinical and pathologic features of these lesions, their differential diagnosis, treatment, and prognostic factors after discussion of the origin, nature and definition of the "intermediate" trophoblast.

Adolescent↗
PubMed1987

Trophoblast-decidual cell interactions and establishment of maternal blood circulation in the parietal yolk sac placenta of the rat.

Implantation sites from rats were studied on days 6, 7, and 8 of pregnancy to determine the sequence of events in the formation of blood spaces in the trophoblast that is part of the parietal wall of the yolk sac placenta and to determine how trophoblast gains access to maternal blood. The maternal blood flowing through these spaces is the source of nutrients that reach the embryo via the visceral endoderm. Tissues were prepared for light microscopy, scanning electron microscopy, and transmission electron microscopy. Trophoblast blood spaces are derived from the lateral intercellular spaces of trophoblast cells and are present in a collapsed condition until day 8, when maternal vessels are tapped by trophoblast. These spaces then contain circulating maternal blood, and trophoblast cells reflect adaptations for metabolic exchange including thinning of trophoblast covering Reichert's membrane and the appearance of numerous fenestrations, with and without diaphragms, in the areas where trophoblast is attenuated. Between days 6 and 7 decidual cells appear to form a barrier between the maternal circulation and trophoblast. On day 7, however, decidual cell processes penetrate the residual uterine luminal epithelial basal lamina, and then the decidual cells that are juxtaposed to trophoblast undergo degradative changes that resemble apoptosis. There is condensation of cytoplasmic contents, fragmentation of the cells, and phagocytosis of the fragments by trophoblast. Some decidual cells are interposed between endothelial cells in the walls of maternal vessels as early as day 7. Trophoblast may gain access to the maternal vessels by replacing decidual cells or by direct imposition of trophoblast cell processes between endothelial cells.

Animals↗