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Original Studies |
INSERM, U-427 (J.L.F., A.T., D.B.-E.), Laboratoire de Génétique Moléculaire (M.V., Y.G.), Centre National de la Recherche Scientifique (D.B.), UPRES-A 8067, Faculté des Sciences Pharmaceutiques et Biologiques, Université René Descartes, 75270 Paris, France; Service d’Hormonologie (J.G., D.P.) and Service de Gynécologie Obstétrique (D.L., P.B.), Hôpital Robert Debré, 75019 Paris, France; and Service de Biochimie, Hôpital Ambroise Paré (F.M.), 92104 Boulogne, France
Address all correspondence and requests for reprints to: Dr. D. Evain-Brion, INSERM U-427, Faculté des Sciences Pharmaceutiques et Biologiques, 4 avenue de l’Observatoire, 75270 Paris Cedex 06, France. E-mail: evain{at}pharmacie.univ-paris5.fr
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In human placenta, the syncytiotrophoblast, which forms the outer layer of the chorionic villi, is an active endocrine unit and secretes its hormonal products into the maternal circulation. Some of these polypeptide hormones are specific to pregnancy, such as hCG, human placental lactogen (hPL), and placental GH (PGH) (7, 8, 9), and can be used as markers of syncytium formation. The syncytiotrophoblast arises in vitro (10, 11) and in vivo (12) from differentiation of villous cytotrophoblasts. These cells aggregate and fuse to form multinucleated syncytiotrophoblasts. The morphological and functional differentiation of cytotrophoblasts into syncytiotrophoblasts can be induced or inhibited by different factors, such as cAMP (13), growth factors such as epidermal growth factor (14) and transforming growth factor-ß (15), polypeptide or steroid hormones such as hCG (16, 17) and dexamethasone (18), and oxygen tension (19, 20). Despite the fact that some maternal serum markers of fetal T21 are of placental origin, little is known of placental defects in Down’s syndrome. Therefore, the aim of this work was to study trophoblast differentiation and endocrine functions in Down’s syndrome.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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French law allows termination of pregnancy with no gestational
age limit when severe fetal abnormalities are observed. Samples of
placental tissues were collected at the time of termination of
pregnancy at 12–35 weeks gestation (expressed in weeks of amenorrhea)
in T21-affected pregnancies and gestational age-matched control cases.
Details of the history of all T21 and control cases are given in Table 1
. Gestational age was confirmed by
ultrasound measurement of crown-rump length at 8–12 weeks gestation.
Fetal Down’s syndrome was diagnosed by karyotyping amniotic fluid
cells, chorionic villi, or fetal blood cells. We checked that placental
tissue was T21 affected by determination of DNA polymorphism markers
(21). In no case was T21 due to translocation, and no mosaicism was
observed. Termination of pregnancy was performed in control cases
affected by severe bilateral or low obstructive uropathy or major
cardiac abnormalities. Fetal karyotype was normal in all controls.
Placental samples were used for cytotrophoblast isolation or were
immediately frozen in liquid nitrogen.
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Total RNA was extracted from frozen placental samples by means
of the single step guanidinium-phenol-chloroform method described by
Chomczynski and Sacchi (22) and from cultured cells following the
procedure of QIAGEN (Courtabeuf, France). The total RNA
concentration was determined at 260 nm, and its integrity was monitored
by 1% agarose gel electrophoresis. Relative messenger RNA (mRNA)
levels of the different genes were measured with the TaqMan 5' nuclease
fluorogenic quantitative PCR assay essentially as previously described
(23). The nucleotide sequences of the primers and probes are listed in
Table 2. Each sample was analyzed in
duplicate, and a calibration curve was run in parallel for each
analysis. The levels of transcripts of the constitutive housekeeping
gene product cyclophilin A were quantitatively measured in each sample
to control for sample to sample differences in RNA concentration and
quality. The PCR data are thus reported as the number of transcripts
per number of cyclophilin A molecules.
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Villous tissue was dissected free of membranes, rinsed, and minced in Ca2+- and Mg2+-free Hanks’ Balanced Salt Solution. Cytotrophoblasts were isolated after trypsin-deoxyribonuclease digestion and discontinuous Percoll gradient fractionation, using a slight modification of the method of Kliman and Alsat (10, 11) adapted for second trimester placentas. The villous sample was submitted to sequential enzymatic digestions, in a solution containing 0.5% powdered trypsin (wt/vol; Difco, Detroit, MI), 5 IU/mL deoxyribonuclease I, 25 mmol/L HEPES, 4.2 mmol/L MgSO4, and 1% (wt/vol) penicillin/streptomycin (Biochemical Industry, Kibbutz Beit Haemek, Israel) in Hanks’ Balanced Salt Solution and monitored under light microscopy. The first and/or second digestion were discarded after light microscopy analysis to eliminate syncytiotrophoblast fragments, and the following four or five sequential digestions were kept. The cells collected during these last digestions were purified on a discontinuous gradient of Percoll (5–70% in 5% steps). The cells that migrated to the middle layer (density, 1.048–1.062 g/mL) were plated on culture dishes (106 cells/cm2), attached to the dishes, and 3 h after plating were carefully washed by three washes with culture medium. After this procedure, we checked that at 3 h of culture, 90–95% of the cells isolated from normal or T21 placentas were cytokeratin 7 positive using a specific monoclonal antibody (dilution, 1:200; DAKO Corp., Trappes, France), less than 0.5% were vimentin positive (dilution, 1:200; Amersham International, Aylesbury, UK), and the other cells were mononucleated and identified as macrophages. None of these cells was hPL positive using a polyclonal specific antibody (dilution, 1:500; DAKO Corp.). Cells were plated in triplicate either on glass slides for immunocytochemistry or onto 60-mm culture dishes (106 cells/cm2). They were cultured for 3 days as previously described (11).
Cell staining
To detect desmoplakin, E-cadherin, cytokeratin 7, or hPL, cultured cells were rinsed with phosphate-buffered saline, fixed, and permeabilized in methanol at -20 C for 25 min. A monoclonal antidesmoplakin or E-cadherin antibody (1:400; Sigma, St. Quentin Fallavier, France) or anti-hPL (1:500; DAKO Corp.) or a polyclonal anticytokeratin 7 (1:200; DAKO Corp.) was then applied, followed by fluorescein isothiocyanate-labeled goat antimouse Ig (Sigma), as previously described (19).
Immunoblotting
To detect hPL, cell extracts were prepared as previously described (19), solubilized protein (5 µg) was immunoblotted using a rabbit polyclonal antibody against hPL (1:250; DAKO Corp.), and the specific band was revealed by chemiluminescence (Supersignal Interchim, Pierce Chemical Co., Bezons, France) after incubation with an antirabbit peroxidase-coupled antibody (19).
Hormone assay
The hCG concentration was determined in culture medium by an enzyme-linked fluorescence assay (Vidas System, BioMerieux, Marcy l’Etoile, France). The assay sensitivity was 2 mU/mL. The hPL concentration was assayed (Amerlex immunoradiometric assay, Amersham Pharmacia Biotech) in maternal serum and in 4-fold concentrated conditioned medium. The assay sensitivity was 0.5 µg/mL. Leptin was determined in 4-fold concentrated conditioned medium using the Sensitive Human Leptin RIA kit (Linco Research, Inc., St. Louis, MO). The assay sensitivity was 0.05 ng/mL. All values are the mean ± SEM of triplicate determinations.
Protein determination
Protein was determined according to Bradford’s method (kit from Bio-Rad Laboratories, Inc., Yvry-sur-Seine, France) using BSA as the standard.
Statistical tests
Statistical analysis was performed using the StatView F-4.5 software package (Abacus Concepts, Inc., Berkeley, CA). Values are presented as the mean ± SEM. Significant differences were identified using Mann-Whitney analysis; P < 0.05 was considered significant.
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Results |
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Isolated cytotrophoblasts from normal placenta aggregate and fuse in vitro within 48–72 h to form a syncytiotrophoblast (10, 11, 13). This is indicated by a gathering of nuclei in a large cytoplasmic mass. In the present study these results were confirmed in 10 different primary cultures of cytotrophoblasts isolated from 10 normal placentas.
In contrast, cytotrophoblasts isolated from 15 different T21-affected
placentas had the same plating efficiency as controls and aggregated,
but did not fuse or fused poorly. After 3 days of culture,
syncytiotrophoblasts were rare, as indicated by immunodetection of
desmoplakin (a desmosomal plaque protein; Fig. 1) and E-cadherin (a cell adhesion
molecule; data not shown). Indeed, desmoplakin and E-cadherin were
absent from normal syncytiotrophoblasts as previously shown (19), but
were present at intercellular boundaries in cultured cells isolated
from T21-affected placentas. This illustrates a decrease and/or delay
in syncytial formation in T21.
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In cells isolated from normal placenta, in vitro
syncytiotrophoblast formation was associated with large increases in
hCG
and hCGß mRNA (Fig. 2), hPL mRNA
(Fig. 3), leptin mRNA, and PGH mRNA (Fig. 4). Concomitantly, hCG (Fig. 2), hPL
(Fig. 3), and leptin (Fig. 4) secretion in culture medium increased
with time. In cells isolated from T21-affected placentas, the defect in
syncytiotrophoblast formation was associated with a clear
decrease in hCG and hCGß mRNA and hCG secretion in culture medium
(Fig. 2) compared to those in normal cells. hPL, leptin, and PGH mRNA
levels were very low. hPL and leptin secretion could not be detected in
culture medium after 3 days. Intracellular hPL was not detected in
T21-affected cells, in contrast to normal cells. Because glucose
inhibits the secretion of placental GH (24), this hormone was not
assayed in culture medium.
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mRNA expression of syncytiotrophoblast hormonal markers in normal and T21-affected placentas
To confirm these in vitro data, we compared, in total
homogenates of eight T21-affected placentas and eight gestational
age-matched controls (12–35 weeks gestation), transcript levels of
these hormones specifically expressed in the syncytiotrophoblast. As
shown in Fig. 5, although levels of the
five transcripts varied greatly from one normal placenta to another,
the expression of these five genes was significantly lower in
T21-affected placentas. Placental samples were homogeneous, as no
significant differences vs. controls were noted in
cytokeratin 7 mRNA (specifically expressed in the epithelial component
of the chorionic villi, i.e. the cytosyncytiotrophoblast),
in pleiotropin (trophoblastic growth factor), or in
ß2-microglobulin levels (ubiquitous gene; Fig. 6). These results suggest a decrease in
functional syncytiotrophoblast mass in T21-affected placenta.
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During pregnancy, massive amounts of hPL are synthesized by the
syncytiotrophoblast and secreted directly into the maternal circulation
(8). We therefore checked whether the defect in functional
syncytiotrophoblasts in T21-affected placentas was associated with a
decreased level of hPL in the maternal circulation. As shown in Fig. 7, we confirmed that hPL levels were
lower in pregnancies with fetal T21 from 14–26 weeks gestation.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In the present study we checked that the fetus and placenta were both T21 affected. Cytotrophoblasts isolated from normal and T21-affected placentas were cultured. We confirmed that in vitro normal cytotrophoblasts aggregate and fuse to form the syncytiotrophoblast (10, 11). This syncytiotrophoblast formation was associated with an increased secretion in culture medium of hCG (7), hPL (8), PGH (9), and leptin (25) as previously shown. We demonstrate in this study that transcript levels of these hormones also increased with cytotrophoblast differentiation. In T21, cytotrophoblasts adhered to culture dishes and aggregated but did not fuse (or fused poorly), as observed by light microscopy, confirming the preliminary observations of Eldar-Geva et al. (26) and as demonstrated here by the expression of E-cadherin and desmoplakin. These results are in agreement with previous macroscopic and histological observations of T21-affected placentas that reveal delayed maturation of chorionic villi and syncytiotrophoblastic hypoplasia with a resistant cytotrophoblastic layer in the third trimester (27, 28).
This decrease in the syncytiotrophoblast functional mass in T21
placentas is further suggested by the results obtained in homogenates
of placental tissues. Indeed, we measured concomitantly by real-time
quantitative RT-PCR the expression of the five hormonal genes
specifically expressed in the syncytiotrophoblast and encoding hormones
secreted in the maternal circulation. In normal placenta, a large
variation in mRNA expression of syncytiotrophoblast hormones was
observed despite the fact that our sampling was homogeneous, as
confirmed by cytokeratin 7, pleiotropin, and
ß2-microglobulin expression levels. Despite
these variations, mRNA expression of hormones (hCGß, hCG, hPL,
PGH, and leptin) specifically expressed in the syncytiotrophoblast
decreased significantly in T21-affected placentas.
In this study we have demonstrated for the first time that in
T21-affected placenta there is a defect and/or delay in the formation
of the syncytiotrophoblast associated with a decrease in hPL, hCG, PGH,
and leptin expression and production. These results do not agree with
the previous study by Eldar-Geva (26), which reported an increase in
hCG and hCGß mRNA in trophoblast cells of a T21-affected placenta.
This discrepancy may be explained by two facts: 1) Eldar-Geva’s study
was based on the comparison of one normal and one T21-affected placenta
that were not gestational age matched; and 2) the cytotrophoblasts in
culture may have been contaminated by fragments of syncytiotrophoblast
(29), as hCG secretion diminished instead of increased with time in
culture. It is crucial to carefully monitor the isolation and
purification of cytotrophoblasts to avoid contamination by
syncytiotrophoblast fragments. Our method including sequential
enzymatic digestion, Percoll gradient purification, and careful washing
of the cells attached to the dish circumvents this problem. Failure to
immunodetect hPL in the plated isolated cells unambiguously excludes
contamination by syncytiotrophoblast fragments.
As anticipated by the results of our in vitro studies, we demonstrated low maternal serum hPL levels in T21-affected pregnancies. Changes in hPL levels during gestation showed that the difference between controls and T21-affected pregnancies was not significant between 15 and 18 weeks. This difference became clearer at 19 weeks and increased up to 24 weeks. This trend paralleled the increase in syncytiotrophoblast mass. These results explain why Ryall et al. observed no differences in maternal serum hPL between 15 and 18 weeks in 48 cases of T21 (30). In contrast to the results of our in vitro studies, maternal hCG levels are elevated in T21-affected pregnancies (5, 6, 31). Our study demonstrates a decrease in the synthesis and secretion of hCG in cultured cells from 10 T21-affected placentas as well as a decrease in hCG transcripts in 8 total placenta extracts in T21. How can we explain this paradox? Maternal levels of hormones of syncytiotrophoblastic origin can be related to transcription as well as to the posttranslational process, which may modify hormonal stability. hCG is a complex of two glycosylated subunits. In T21, hCG may be subject to posttranscriptional changes, as suggested by Brizot et al. (32, 33) and recently confirmed by reports of a hyperglycosylated form of hCG in Down’s syndrome (34, 35). This hyperglycosylated form may have a different half-life, thus explaining elevated maternal levels. In contrast, hPL is not glycosylated, and the decrease in its synthesis and secretion was directly reflected by a decreased level in the maternal serum after 19 weeks gestation.
In conclusion, we have demonstrated that 1) there is an abnormal formation of the syncytiotrophoblast in Down’s syndrome; 2) there is therefore a decrease in the production of pregnancy-specific polypeptide hormones by the placenta in Down’s syndrome. This finding will enhance understanding of the maternal hormonal changes of placental origin that are used as markers of fetal Down’s syndrome and will be of help in finding new markers of placental origin. The syncytiotrophoblast plays a key functional role during pregnancy. Better knowledge of its alterations in T21 may therefore be useful in understanding some aspects of fetal development in Down’s syndrome.
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Acknowledgments |
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Footnotes |
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Received March 4, 2000.
Revised June 1, 2000.
Accepted June 27, 2000.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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0.001.
The data shown are from one representative experiment. B, Mean hCG
secretion in the culture medium of 8 primary cultures of 8 control
placentas (N) and 10 primary cultures from 10 T21-affected placentas
(T21). The results are expressed as the mean ± SEM of
three culture dishes at each time in culture.
) and T21-affected pregnancies (
). The number
of individual assays for each gestational stage is indicated next to
each point. ***, P < 0.001.