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PubMed2006

Early embryonic demise: no evidence of abnormal spiral artery transformation or trophoblast invasion.

Invasion by extravillous trophoblast of uterine decidua and myometrium and the associated spiral artery 'transformation' are essential for the development of normal pregnancy. Small pilot studies of placental bed and basal plate tissues from miscarriages have suggested that impaired interstitial and endovascular trophoblast invasion may play a role in the pathogenesis of miscarriage. The hypothesis that early miscarriage is associated with reduced extravillous trophoblast invasion and spiral artery transformation was tested in a large series of placental bed biopsies containing decidua and myometrium and at least one spiral artery from early, karyotyped embryonic miscarriages (<or=12 weeks' gestation; n = 50) dated from the last menstrual period and ultrasound scan dated normal pregnancies (n = 78). Frozen sections were immunostained to demonstrate trophoblast (cytokeratin), myometrium and spiral artery medial smooth muscle (desmin), and endothelium (von Willebrand factor). Trophoblast invasion and individual features of spiral artery transformation were assessed histologically in spiral arteries of miscarriages (n = 176) and controls (n = 246) and analysed statistically using a logistic regression model. Trophoblast invasion of uterine tissues and spiral artery transformation did not differ between euploid and aneuploid early miscarriage and also did not differ significantly from normal pregnancy. These findings suggest that failed trophoblast invasion and spiral artery transformation do not have a pivotal role in the pathogenesis of early miscarriage.

Abortion, Spontaneous↗
PubMed2006

Late sporadic miscarriage is associated with abnormalities in spiral artery transformation and trophoblast invasion.

Trophoblast invasion of uterine decidua and myometrium, and spiral artery transformation, are essential for the development of normal pregnancy; this process is impaired in pre-eclampsia, fetal growth restriction, and pre-term labour. The hypothesis that late miscarriage is associated with reduced trophoblast invasion and spiral artery transformation was tested in a large series of placental bed biopsies containing decidua and myometrium from late, karyotyped, embryonic miscarriage (>or=13 weeks' gestation; n = 26; n = 96 spiral arteries) and gestationally matched ultrasound-dated normal pregnancies (n = 74; n = 236 spiral arteries). Cryostat sections were immunostained using an avidin-biotin peroxidase technique for cytokeratin, desmin, and von Willebrand factor to detect trophoblast, myometrium, and vascular smooth muscle and endothelium, respectively. Trophoblast invasion and individual features of spiral artery transformation were assessed and analysed using a logistic regression model. Compared with normal pregnancy, myometrial spiral arteries in late miscarriage showed reduced endovascular (4% vs. 31%, p = 0.001) and intramural trophoblast (76% vs. 88%, p = 0.05), and less extensive fibrinoid change (4% vs. 18%, p = 0.01). In contrast, endovascular trophoblast in decidual spiral arteries was increased (40% vs. 66%, p = 0.04). These findings suggest that, in common with pre-eclampsia, late sporadic miscarriage may be associated with reduced trophoblast invasion and inadequate transformation of myometrial spiral arteries.

Abortion, Spontaneous↗
PubMed1998

Placental 57-kDa Ca(2+)-binding protein: regulation of expression and function in trophoblast calcium transport.

During gestation, transport by placental trophoblasts is solely responsible for nutrient supply to the developing fetus. The calcium (Ca) transport machinery of the placenta thus represents the primary tissue site for regulating fetal Ca homeostasis. The exact mechanism of trophoblast Ca transport is not known. However, there is evidence suggesting that a developmentally expressed cytosolic, trophoblast-specific, high M(r) 57-kDa Ca-binding protein (CaBP) plays an important role in regulating and/or shuttling cytosolic Ca. We report here the cloning of a full-length cDNA of the mouse CaBP which shows significant homology with calreticulin, an endoplasmic reticulum-associated Ca binding protein. The functional role of CaBP in cellular Ca handling was investigated using a trophoblastic cell line, Rcho-1, derived from a rat choriocarcinoma. Upon differentiation, Rcho-1 cells exhibit enhanced Ca uptake compared to undifferentiated Rcho-1 stem cells, and CaBP expression is upregulated. To analyze the regulation of CaBP expression, placenta organ cultures and Rcho-1 cells were treated for 48 h in vitro with a series of agents implicated in Ca homeostasis. In both placenta organ cultures and undifferentiated as well as differentiated Rcho-1 cells, treatment with 1,25-dihydroxy vitamin D3, estrogen, parathyroid hormone (PTH), parathyroid hormone-related protein (PTHrP 1-34), and Ca had no effect on CaBP mRNA and protein levels, which were significantly stimulated by PTHrP 67-84. PTHrP 67-84-treated Rcho-1 cells also exhibited higher Ca uptake activity than untreated control cells. The upregulation of CaBP expression during and/or following the differentiation of Rcho-1 cells into trophoblastic giant cells supports the importance of CaBP in trophoblast maturation and the validity of the Rcho-1 rat model cell system. In addition, the action of PTHrP on placental trophoblast Ca transport is likely to involve the regulation of CaBP expression to handle the increasing Ca requirements of the developing fetus.

Amino Acid Sequence↗
PubMed1999

Functional analysis of placental 57-kDa Ca(2+)-binding protein: overexpression and downregulation in a trophoblastic cell line.

The placental trophoblastic epithelium functions to transport nutrients needed by the fetus, including calcium, which is required in the greatest amounts during the last third of pregnancy when the majority of fetal skeletal mineralization occurs. The mechanism of placental calcium transport and the developmental changes in the trophoblast that facilitate this process are currently incompletely understood. We have previously identified a 57-kDa, Ca(2+)-binding protein (CaBP) functionally implicated in placental calcium transport and trophoblast differentiation. In this study we have directly examined the role of CaBP in these processes by (1) recombinantly overexpressing CaBP in an inducible manner and (2) downregulating CaBP expression using antisense technology, using the rat choriocarcinoma cell line Rcho-1 as a trophoblastic cell model system. Our results show that overexpression of CaBP stimulates both cellular calcium uptake and vectorial calcium transport activities in Rcho-1 cells. Those cells stably expressing CaBP also exhibit higher levels of steady-state intracellular calcium and enhanced calcium-buffering ability. In addition, prolonged overexpression of CaBP in Rcho-1 cultures promotes trophoblast differentiation. Conversely, downregulation of CaBP expression had a negative effect on calcium uptake, calcium transport, and trophoblast differentiation in Rcho-1 cells. These data indicate that CaBP plays a direct role in placental calcium transport, functioning both as an intracellular calcium buffer and as a shuttle. These results also support a more direct role for CaBP in the trophoblast differentiation pathway.

Animals↗
PubMed2001

Trophoblast giant-cell differentiation involves changes in cytoskeleton and cell motility.

Trophoblast giant-cell differentiation is well-characterized at the molecular level, yet very little is known about how molecular changes affect the cellular functions of trophoblast in embryo implantation. We have found, using both explanted E7.5 mouse embryo ectoplacental cone and the rat choriocarcinoma (Rcho-1) cell line, that trophoblast differentiation is distinguished by dramatic changes in cytoarchitecture and cell behavior. Undifferentiated trophoblast cells contain little organized actin and few small, peripheral focal complexes and exhibit high membrane protrusive activity, while differentiated trophoblast giant cells contain prominent stress fibers, large internal as well as peripheral focal adhesions, and become immotile. The dramatic changes in cell behavior and cytoskeletal organization of giant cells correlate with changes in the activities of the Rho family of small GTPases and a decrease in tyrosine phosphorylation of focal adhesion kinase. Together, these data provide detailed insight into the cellular properties of trophoblast giant cells and suggest that giant-cell differentiation is characterized by a transition from a motile to a specialized epithelial phenotype. Furthermore, our data support a phagocytic erosion, rather than a migratory infiltration, mechanism for trophoblast giant-cell invasion of the uterine stroma.

Actins↗
PubMed1995

Functional role of cell surface integrins on human trophoblast cell migration: regulation by TGF-beta, IGF-II, and IGFBP-1.

Trophoblast invasion of the human uterus is stringently controlled by the microenvironment. Invasive extravillous trophoblast cells in situ as well as in culture express a selective repertoire of cell surface integrins. Since migration is a necessary step in the invasion cascade, we tested whether certain integrins or invasion-regulating molecules, i.e., TGF-beta, IGF-II, and IGFBP-1 produced at the fetomaternal interface had a functional role on trophoblast migration. Flow cytometric analysis of integrin expression and the use of an in vitro cell migration assay revealed that exogenous TGF-beta upregulates integrin expression and reduces migratory ability to the invasive trophoblast, whereas IGF-II has no effect on integrin expression but stimulates migration. Trophoblast migration was inhibited in the presence of alpha 5 and beta 1 integrin blocking antibodies, indicating its dependence on the expression of these subunits. Furthermore, IGFBP-1, which contains an RGD sequence recognizing certain integrins, stimulated migration, an effect that was blocked by pretreatment with anti-alpha 5 or -beta 1 blocking Abs. These studies demonstrate that the migration of first trimester invasive trophoblast in vitro (1) requires the expression of alpha 5 and beta 1 integrin subunits, (2) is inhibited by TGF-beta, possibly due to increased cell adhesiveness to the extracellular matrix, (3) is stimulated by IGF-II by an as yet undetermined mechanism, and (4) is stimulated by IGFBP-1, likely by interaction with the RGD binding site of the alpha 5 beta 1 integrin. The invasion-regulating effects of TGF-beta, IGF-II, and IGFBP-1 may thus, at least in part, be due to their migration-regulating effects on the invasive trophoblast.

Antibodies↗
PubMed1995

Physiological dilation of uteroplacental arteries in the guinea pig depends on nitric oxide synthase activity of extravillous trophoblast.

The trophoblast invasion of uteroplacental arteries in the guinea pig has been studied by means of electron microscopy and immunohistochemisty. To identify trophoblast cells, smooth muscle cells, and endothelial cells, antibodies against cytokeratins, smooth muscle myosin, desmin, and vimentin were employed. Furthermore, the immunohistochemical expression patterns of nitric oxide synthase isoforms (eNOS, mNOS and bNOS) were studied and were compared with the enzyme histochemical staining for NADPH-diaphorase. Dilation of uteroplacental arteries begins prior to day 30, when trophoblast cells that coexpress endothelial and macrophage nitric oxide synthase can be found in the vicinity of the vessels and replace the surrounding peritoneal mesothelium. Trophoblast invasion of the arterial walls and the subsequent wall destruction are only secondary effects. Starting around day 50, the final steps of pregnancy-dependent vessel modifications involve intraarterial trophoblast adhesion to the endothelium and subsequent replacement of the endothelium by the trophoblast cells. These may centrifugally invade the vessel media eventually forming intraluminal plugs. These findings led us to the conclusion that in the guinea pig pregnancy-induced physiological dilation of the uteroplacental arteries is due to the effect of nitric oxide rather than being caused by trophoblast-induced media destruction.

Animals↗
PubMed1985

Quantitative morphology. A study of the trophoblast.

It is difficult to predict the possible development of a malignant trophoblastic tumor after the evacuation of a hydatidiform mole. In order to help resolve this difficulty, a morphometric study has been carried out. The mean nuclear area of the trophoblast in a group of hydatidiform moles, followed by a trophoblastic malignancy, was found to be statistically significantly larger than that of the trophoblast in a group of hydatidiform moles which were not followed by malignant trophoblastic disease. However, the mean trophoblast/nontrophoblast ratio in villi demonstrated no statistically significant difference between those 2 groups of hydatidiform moles. Therefore it is not advisable to grade hydatidiform moles on the basis of trophoblastic proliferation alone. It is suggested that the trophoblastic lining of hydropic villi in the placental tissue of hydatidiform moles has malignant features already, but these are more pronounced in those hydatidiform moles which are subsequently followed by a choriocarcinoma.

Choriocarcinoma↗
PubMed1991

Bovine trophoblastic cell vesicle attachment to polarized endometrial epithelial cells in vitro.

Interactions between bovine trophoblastic cell vesicles and bovine endometrial epithelial cells were investigated by light and electron microscopy and lectin histochemistry in a cell culture model of early blastocyst attachment. Primary lines of bovine endometrial epithelial cells were polarized by subculturing on substrata and maintaining cultures at the air-medium interface. Trophoblastic cell vesicles were obtained from elongated Day 14 blastocysts. In co-cultures, trophoblastic cell vesicles adhered to endometrial epithelial cells through microvillus interdigitation and formation of primitive membrane junctional complexes. After 3 d in co-culture, a multilayered cellular plaque formed at the trophoblastic cell-endometrial epithelial cell interface. The type of cells contributing to this local proliferative response could not be identified specifically as trophoblastic or endometrial cells, and areas of membrane fusion between cells were noted. Ultrastructural features of vesicle adhesion in cultures were similar to features of conceptus attachment in vivo. Lectins bound to apical membranes of trophoblastic cells and endometrial epithelial cells in all locations except contact sites between vesicles and endometrial cells. These findings suggest that local cellular proliferation and membrane fusion between trophoblastic and endometrial epithelial cells may be early events in conceptus implantation in the cow and these events can be reproduced in culture.

Animals↗
PubMed2004

Glycodelin A and differentiation of first trimester trophoblast cells in vitro.

AIM: The glycoprotein, glycodelin A (GdA) is a main product of the maternal decidua in the first trimester of pregnancy and is secreted into the amniotic fluid. The purpose of this study was to investigate the effect of GdA on secretion and surface markers of isolated first trimester trophoblasts in vitro. METHODS: Cytotrophoblasts were prepared from human first trimester placentae and incubated with varying concentrations of GdA or transfected separately with the expression plasmid of GdA. Supernatants were assayed for human chorionic gonadotropin (hCG) protein concentrations. Expression of human placental lactogen (hPL), mucin 1 (MUC1) and the Thomsen-Friedenreich (TF) epitope was analysed in stimulated trophoblast cells and in unstimulated controls by immunocytochemistry. RESULTS: Glycodelin A induced a reduced expression of hPL compared with unstimulated controls. Expression of MUC1 was not affected by GdA. Freshly isolated trophoblast cells showed no TF expression but became positive for this antigen after 96 h of cultivation. GdA-stimulated trophoblast cells inhibited TF expression after 96 h of cultivation. GdA plasmids induced a significantly higher hCG production in transfected cells than in cells transfected with the empty plasmid. CONCLUSIONS: The results obtained in this study suggest that GdA is involved in the differentiation of trophoblast cells. The treatment of GdA plasmid transfected trophoblast cells stimulated hCG production in isolated trophoblast cells and inhibited hPL and TF expression, suggesting a functional link between hCG and GdA.

Adult↗
PubMed2005

Regulation of progesterone production in human term trophoblasts in vitro by CRH, ACTH and cortisol (prednisolone).

BACKGROUND: In most mammals, onset of labor is accompanied with progesterone withdrawal. In humans, cortisol blockade of progesterone is a possible mechanism involved in the initiation of labor. Therefore, aim of the study was to clarify the effect of CRH, ACTH and cortisol (prednisolone) on the release of progesterone by term trophoblast cells in vitro. METHODS: Cytotrophoblast cells were prepared from human term placentas by standard dispersion of villous tissue followed by a percoll gradient centrifugation step. Trophoblasts were incubated with CRH, ACTH as well as with prednisolone. RESULTS: The release of progesterone is decreased in CRH- and ACTH-treated trophoblast cell cultures compared to untreated trophoblast cells. Addition of prednisolone in varying concentrations leads to an increase of trophoblast progesterone production. CONCLUSIONS: The results suggest that CRH and ACTH directly modulate the endocrine function of trophoblasts in culture by downregulating progesterone production. Prednisolone on the other hand showed a stimulating effect on progesterone production in term trophoblast cells in vitro. Because blockade of progesterone is a possible mechanism involved in initiation of labor, we may speculate that CRH and ACTH are directly involved in the auto- or paracrine regulation of this procedure.

Adrenocorticotropic Hormone↗
PubMed2002

Expression of the Thomsen-Friedenreich antigen and of its putative carrier protein mucin 1 in the human placenta and in trophoblast cells in vitro.

The Thomsen-Friedenreich (TF) antigen (or, more precisely, epitope Galbeta1-3GalNAcalpha-O-) has been known for a long time as a carcinoma-associated antigen. In normal tissues the occurrence of TF antigen is restricted to a few immunologically privileged areas. Here we report on the identification of the TF epitope and its putative carrier protein mucin 1 (MUC1) in human placental tissue, on isolated trophoblast cells in vitro and on trophoblast tumour cell lines BeWo and Jeg3. Cryosections of placental and decidual tissues of the first, second and third trimester were double stained with monoclonal antibodies directed against the TF epitope (IgM) and against MUC1 (IgG). In the first trimester of pregnancy we found strong expression of TF antigen and MUC1 at the apical side of the syncytiotrophoblast directed towards the maternal blood. This expression was consistent in the second trimester of pregnancy, and to a lesser degree in the third trimester. In addition, we found positive staining for TF antigen and MUC1 on extravillous trophoblast cells in the decidua during the first and second trimester of pregnancy. Trophoblast tumour cells of the cell line BeWo, which form a syncytium in vitro, were also positive for TF antigen and MUC1, whereas Jeg3 cells, which are unable to form a syncytium, expressed only MUC1. Freshly isolated trophoblast cells from first trimester placentas showed strong staining for MUC1; however, only a few of these cells (less than 1%) were positive for TF antigen, and might consist of digested fragments of the syncytium. In summary, TF antigen and MUC1 are expressed by the syncytiotrophoblast at the feto-maternal interface and by extravillous trophoblast cells invading the decidua, whereas villous cytotrophoblast cells in situ as well as freshly isolated trophoblast cells from first trimester placentas only express MUC1 but not TF antigen.

Antigens, Tumor-Associated, Carbohydrate↗
PubMed2002

Invasive depth of extravillous trophoblast correlates with cellular phenotype: a comparison of intra- and extrauterine implantation sites.

During intrauterine human placentation, extravillous trophoblast invades uterine tissues starting with proliferating stem cells at the basement membrane of anchoring villi. Transition to the postproliferative invasive phenotype takes place several cell layers distant. Here we show that in intrauterine pregnancies invasive trophoblast comprises three cellular phenotypes: a. Small spindle-shaped trophoblast cells are found along the whole invasive pathway throughout pregnancy. They are embedded in little heterogeneous extracellular matrix but expose only fibronectin receptors (integrins alpha5beta1, alphavbeta3/5), resulting in a partial integrin-matrix mismatch. b. Large polygonal trophoblast cells are rare in early pregnancy but increase in number towards term. They secrete ample heterogeneous extracellular matrix and expose integrins specifically matching the opposing matrix molecules (integrins alpha6beta4, alpha5beta1). c. Multinucleated giant cells in all stages of pregnancy form a kind of peripheral shell of trophoblast. In contrast to intrauterine pregnancies, in viable tubal pregnancies, Mib-1 expression indicating proliferation, extends deeply into the invasive pathway. Trophoblast cells of the invasive pathway mostly belong to the small spindle-shaped phenotype and secrete little extracellular matrix, mainly fibronectins. At the transition to the second cellular layer of cell columns expression of integrin alpha6beta4 switches to expression of alpha5beta1 and alphavbeta3/5. Viable tubal pregnancies are characterised by a broad overlap of proliferative with invasive phenotype as well as a general integrin-matrix mismatch. The differences in proliferation patterns, cellular phenotype and matrix-integrin co-localisation may well explain the increase of invasiveness of normal extravillous trophoblast from term intrauterine via early intrauterine to viable tubal pregnancies.

Cell Count↗
PubMed2004

Cytoskeletal filaments and associated proteins during restricted trophoblast invasion in bovine placentomes: light and transmission electron microscopy and RT-PCR.

Trophoblast cell migration is unusual in epitheliochorial placentae but occurs in placentomes of cows as "restricted" trophoblast invasion of binucleated trophoblast giant cells (TGC). Migration may be induced by integrin binding to the extracellular matrix initiating two pathways: (1) conformational changes of the actin cytoskeleton induced by an accumulation of its associated proteins and (2) integrin-dependent phosphorylation of various protein kinases. In cow placentomes, actin, its associated proteins (alpha-actinin, vinculin) and a key protein kinase of the signal transduction cascade (phosphorylated mitogen-activated protein kinase, pMAPK) were localized by immunogold-silver enhancement and immunoperoxidase staining at the light- and transmission electron-microscopical levels. Findings were confirmed by amplification of specific mRNA transcripts by reverse transcriptase/polymerase chain reaction. Actin and alpha-actinin were co-localized apically in mononuclear trophoblast cells, along the cytoplasmic membrane of TGC and apically in maternal crypt cells. The actin and alpha-actinin immunoreaction occurred as a band of electron-dense particles beneath the cytoplasmic membrane. Vinculin labelling was membrane-associated in TGC and in fetal and maternal endothelial cells. MAPK was observed as nuclear clusters in both kinds of trophoblast cells and was less dense in single uterine epithelial cells. Most MAPK immunoreactivity was detected in the nuclei of the trophoblast epithelium but was also sometimes membrane-associated in the cytoplasm. Thus, actin, alpha-actinin, MAPK and vinculin may be involved in the regulation of TGC migration. "Restricted" trophoblast invasion could serve as a model for invasive processes.

Actins↗
PubMed1988

Discordance in deoxyribonucleic acid analysis of fetus and trophoblast.

Molecular analysis of deoxyribonucleic acid extracted from trophoblast has become an important component of modern prenatal diagnosis. Discrepancies between trophoblast and fetal tissue in both chromosomal and metabolic analysis have been reported. We studied 50 paired fetal and trophoblast deoxyribonucleic acid specimens with a highly polymorphic probe for repetitive "minisatellite" regions of deoxyribonucleic acid that may be areas of high recombination. Four pairs showed persistent variations in bands consistent with differences in fetal and trophoblast deoxyribonucleic acid. Discordance in trophoblast deoxyribonucleic acid as a reflection of fetal genotype may be secondary to mitotic recombination or sister chromatid exchange in the trophoblast, and the possibility of discordance must be considered in interpreting the results of prenatal diagnostic testing on trophoblast specimens.

DNA↗
PubMed1990

Diagnostic and therapeutic curettage in gestational trophoblastic disease.

From June 1976 through June 1989, 37 nonconsecutive patients underwent uterine curettage during the course of their gestational trophoblastic disease. In 22 patients (59%) trophoblastic tissue was obtained. Three (8.1%) patients sustained a uterine perforation during the procedure. In six patients curettage was performed for bleeding. There were six patients curetted during assessment for metastatic trophoblastic disease. Twenty-eight patients underwent curettage for the presumed diagnosis of nonmetastatic gestational trophoblastic disease. In retrospect, four of these women (14.3%) had insufficient criteria for the diagnosis of gestational trophoblastic disease. Of the remaining 23 patients, four (17.4%) went into clinical remission without further treatment. Ten patients (43.5%) had a transitory decline in serum beta-human chorionic gonadotropin levels that subsequently rose or plateaued. Six patients (26.1%) showed no effect from the curettage on their serum beta-human chorionic gonadotropin trend during a short period of observation. Three patients (13.0%) with nonmetastatic gestational trophoblastic disease were not observed for a possible therapeutic effect after curettage. Thus, in only 4/20 (20%) women with nonmetastatic trophoblastic disease was a therapeutic effect from curettage shown.

Chorionic Gonadotropin↗
PubMed1989

PGE2-mediated immunosuppression by first trimester human decidual cells blocks activation of maternal leukocytes in the decidua with potential anti-trophoblast activity.

We have earlier shown that first trimester human decidual cells and decidual macrophages suppress T lymphocyte alloreactivity in an MHC-unrestricted manner by secreting PGE2, which blocks the generation of IL-2 receptors (IL-2R) and production of IL-2 by lymphocytes but does not interfere with the interaction between IL-2 and IL-2R or the lytic function of CTL, once generated. The present study examined whether these events constituted a physiological, immunoprotective mechanism in situ against the activation of maternal decidua-infiltrating leukocytes with potential anti-trophoblast cytocidal function. We examined (1) whether there was IL-2R expression, IL-2 production, or anti-trophoblast killer activity in short-term (0-3 day) cultures of collagenase-dispersed first trimester human decidua inclusive of leukocytes; (2) if not, whether any of these parameters could be stimulated in these cultures by blocking PGE2 synthesis with indomethacin, or neutralizing PGE2 with anti-PGE2 antibody; (3) whether exogenously added recombinant IL-2 in the presence or absence of indomethacin stimulated IL-2R expression or anti-trophoblast killer function in these cultures. IL-2R (as defined by Tac antigen) was measured in the whole cell population by a radioimmunoassay and further examined at the cellular level with radioautography. IL-2 production in culture supernatants was measured from the proliferative response (3HTdR uptake) of an IL-2-dependent (CTLL) cell line. Killer activity in fresh or cultured decidua-associated cells as well as PBL of normal or pregnant subjects was measured against 51Cr-labeled targets inclusive of autologous cytotrophoblast cells or long-term human trophoblast cell lines, K562 and Daudi cells. Results revealed a complete absence of IL-2R expression, IL-2 production, or anti-trophoblast killer activity in the untreated cultures of the decidua, but all these parameters were significantly stimulated in the presence of indomethacin or anti-PGE2 antibody. The indomethacin-stimulated killer cells had NK-like activity. Presence of high dose exogenous IL-2 alone in these cultures strongly stimulated IL-2R expression and anti-trophoblast killer function, which were augmented further in the additional presence of indomethacin. The resultant killer cells had LAK cell-like activity. These findings suggest that PGE2 secretion by first trimester human decidual cells blocks activation of maternal leukocytes in the decidua with potential anti-trophoblast killer function, by inhibiting IL-2 receptor generation and IL-2 production in situ.

Cytotoxicity, Immunologic↗
PubMed1992

Induction of manganese superoxide dismutase in cultured human trophoblast during in vitro differentiation.

The antioxidant responses of human cell differentiation and membrane fusion are not known and may be important in understanding cellular response to injury in the human placenta. We studied the regulation of antioxidant enzymes in human trophoblasts which differentiate from mononucleated cellular trophoblasts to synctium in vivo and in culture. We characterized morphological and biochemical differentiation of cultured trophoblasts from term placenta in the presence or absence of serum, on different growth surfaces, and with a range of plating densities. Culture of cellular trophoblasts consistently and transiently induced the mRNAs of the mitochondrial antioxidant manganese superoxide dismutase (Mn SOD) but not the mRNAs for the antioxidant enzymes copper zinc SOD or catalase. Fibrin and type I collagen substrates modulated only the expression of the placental specific proteins, human chorionic gonadotropin, and human placental lactogen. Both Mn SOD induction and terminal differentiation, as reflected by human chorionic gonadotropin expression, were dependent on trophoblastic plating density. Increased levels of a smaller Mn SOD mRNA species correlated temporally with an increase in Mn SOD enzyme activity in cultured trophoblasts. These results demonstrate that Mn SOD gene expression and enzyme activity precede or are coordinately regulated with morphological and biochemical trophoblastic differentiation.

Antioxidants↗