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CIHR Group in Fetal and Neonatal Health and Development and Departments of Physiology and Obstetrics and Gynecology, University of Toronto, Toronto, Ontario, Canada M5S 1A8
Address all correspondence and requests for reprints to: Dr. Ping Xu, 1 King’s College Circle, Medical Sciences Building, Room 3344, Department of Physiology, University of Toronto, Toronto, Ontario, Canada M5S 1A8. E-mail: . ping.xu{at}utoronto.ca
Abstract
Extensive extracellular matrix (ECM) remodeling is found in many processes during human parturition at term and preterm. These include cervical ripening, fetal membrane rupture, and placental detachment from the maternal uterus. Matrix metalloproteinases (MMPs) are the main mediators of ECM degradation. The present study was designed to investigate the expression of MMP-2 and MMP-9 in human fetal membranes (FMs) and placental (PL) tissues with or without labor at preterm and term parturition. Both zymography and Western blot analysis showed that MMP-9 was significantly (P < 0.01) increased in preterm and term labor FM, compared with nonlabor. Term labor PL also had a much higher (P < 0.05) level of MMP-9 than that of term nonlabor. No significant difference in MMP-2 expression was found between labor and nonlabor tissues. Immunolocalization studies revealed a specific distribution pattern for MMP-2 and MMP-9. MMP-2 was localized to the amnion mesenchyme, chorion laeve trophoblast, decidua parietalis, and blood vessels in PL villi. MMP-9 was localized mainly to amnion epithelia, chorion laeve trophoblast, decidua parietalis, and PL syncytiotrophoblasts. Separate cell culture from different layers of FM and culture of purified PL trophoblast cells showed that PL syncytiotrophoblast and amnion epithelial cells exclusively produced MMP-9; chorion trophoblast cells secreted both MMP-2 and MMP-9, but amnion mesenchymal cells produced only MMP-2. We concluded that MMP-2 and MMP-9 exhibited cell-specific expression in the human PL. An increase in MMP-9 expression may contribute to degradation of the ECM in the FM and PL, thereby facilitating FM rupture and PL detachment from the maternal uterus at labor, both preterm and term.
EXTENSIVE EXTRACELLULAR MATRIX (ECM) remodeling is important in the processes of preterm and term human parturition. These events include cervical ripening, fetal membrane rupture, and placental detachment from the maternal uterus (1, 2, 3). The fetal membranes represent a complex multilaminate tissue, composed of the amnion and chorion. These two closely adherent layers consist of several cell types, including epithelial cells, mesenchymal cells, and cytotrophoblast cells. The tensile strength of the fetal membranes depends on the integrity of these cells and their associated ECM (4, 5, 6). Intensive disruption of the constituents in ECM may be associated with the rupture of fetal membranes both spontaneously and prematurely (7, 8, 9). Most of the ECM and basement membrane components can be degraded by matrix metalloproteinases (MMPs), a group of structurally related, zinc-dependent enzymes (10). These include MMP-2 and MMP-9 (also known as gelatinase A and B), which are capable of digesting collagen Iv, a major component of basement membrane. These two MMPs have been identified in human fetal membranes and amniotic fluid. An increase in MMP-9 levels in the fetal membranes and amniotic fluid has been associated with term labor (11, 12, 13), indicating a role for MMP-9 in human parturition. However, there is little information concerning changes in MMP level with spontaneous preterm labor, and the cell sites of MMP-2 and MMP-9 expression are not clearly known.
During normal pregnancy, the placental basal villi are tightly attached to the decidual tissue to anchor the placenta within the uterus. This attachment depends on cell-cell and cell-ECM interaction. Therefore, as parturition occurs, detachment of the placenta requires ECM degradation in which MMPs are involved (14). Because of the significance of preterm and term fetal membrane rupture and delivery as events within the labor processes, we have compared the production of MMP-2 and MMP-9 in human fetal membranes and placenta with or without labor at term and preterm. We hypothesized that there would be cell-specific expression of these enzymes within the membrane and placenta, this would change in association with the process of labor, and alterations in MMPs expression would reflect the process of labor, independent of the time of pregnancy that this occurred.
Materials and Methods
Tissue collection
Fetal membranes were collected at preterm (30–34 wk) labor (n = 8) and nonlabor (n = 7) and term (38–41 wk) labor (n = 8) and nonlabor (n = 8). The indications for preterm nonlabor patients in this study were antepartum hemorrhage, thyroid disorder, and gestational diabetes. None of the patients from whom specimens were obtained had received corticosteroids. Tissues from patients with documented infection were not included. Pieces of tissue were taken from the edge of the ruptured membranes in delivered specimens, or as far as possible, from a corresponding area of the membranes away from the placenta in elective cesarean section specimens. Several aliquots of tissue were removed randomly from the maternal side of the placenta, collected from term (38–41 wk) labor (n = 8) and nonlabor (n = 8) patients. The tissues were snap frozen in liquid nitrogen and stored at -80 C. Patient consent and ethical approval were obtained before tissue collection in accordance with the Canadian Tri-council guidelines and the regulations of Mount Sinai Hospital, Toronto, and the University of Toronto.
Cell purification and culture
Placental and chorionic trophoblast cell cultures. Placental and chorionic trophoblast cells were prepared using a modification of the method of Kliman et al. (15), as described previously (16). Briefly, term human placenta (n = 6) and chorion tissue (n = 5) were obtained from uncomplicated pregnancies after elective cesarean section in the absence of labor. The placental tissue was pooled and digested with 0.125% trypsin (Sigma, St. Louis, MO) and 0.02% DNase I (Sigma) in DMEM (Life Technologies, Inc., Grand Island, NY) containing 0.1% BSA, 0.005% gentamicin, and 0.01% streptomycin three times for 30 min each. The chorion with adherent decidua was peeled away from the amnion and digested three times for 60 min each time with DMEM as above, containing 0.2% collagenase (Sigma) without DNase I. The placental or chorion/decidual cells were loaded onto a 5–75% Percoll (Sigma) gradient at step increments of 5% Percoll and then centrifuged at 37 C and 2500 x g for 20 min to separate different cell types. Cytotrophoblasts between the density markers of 1.049 and 1.062 g/ml were collected and plated at a density of 106 cells/ml per well in DMEM culture medium containing 10% FCS (Life Technologies, Inc.). The cells were cultured for 3 d at 37 C in 5% CO2:95% O2. Under these conditions the placental cells aggregate to form a syncytium, whereas the chorionic trophoblast cells form clumps or remain as single cells. Cultures were immunostained to determine the proportion of cytokeratin (an epithelial cell marker) or vimentin (a fibroblast cell marker) positive cells and were counterstained with Carazzi’s hematoxylin. About 95% of placental cells and 90% of chorionic cells were cytokeratin positive (16).
Isolation and culture of amnion cells. Term (38- to 40-wk gestation) placenta with attached fetal membranes were collected immediately following elective caesarean section (n = 5 patients). The amnion was peeled from the chorion, cut approximately 2 cm from the placenta disk and washed in PBS (Dulbecco’s PBS, pH 7.5; Life Technologies, Inc./BRL, Burlington, Ontario, Canada). Approximately two-thirds of the amnion was minced finely with scissors, transferred to 50 ml DMEM containing collagenase A (1 mg/ml) (Roche Molecular Biochemicals Canada, Dorval, Quebec, Canada) and incubated at 37 C with gentle shaking for 2 h. The remaining amnion was placed in a 250 ml tissue flask containing 0.25% trypsin (Life Technologies, Inc.) in DMEM and incubated for 20 min at 37 C with gentle shaking. The first digestion supernatant was discarded; the tissue was then incubated with two subsequent 30-min washes of digestion media. After digestion, the suspension was filtered through 100-micron nylon mesh; cells were pelleted by centrifugation at 2500 g for 10 min. The pellet was resuspended in 3 ml DMEM and layered on a discontinuous Percoll gradient (5%/20%/40%/60% vol/vol). The gradient was then centrifuged at 800 g for 20 min. A single band of cells was identified from approximately the 20% Percoll level and these were aspirated. The cells were washed in DMEM, counted on a hemocytometer, and suspended in DMEM supplemented with 10% FCS (Life Technologies, Inc.) and antibiotics (1000 U/ml penicillin/0.1 mg/ml streptomycin/0.23 µg/ml, Amphotericin, Sigma). The cells were plated in 8-well chamber slides (Labtek, Nunc, Naperville, IL) at a density of 250,000 cells/500 µl/well. Cells were maintained in culture at 37 C in 5% CO2:95% O2. After 3 d of culture, the media was removed and replaced with fresh media without FCS for another 24-h culture. The media was then collected and stored at -20 C. The cells were fixed with 4% paraformaldehyde and stored in 70% ethanol for further analysis. Amnion cells were characterized using antibodies to cytokeratin and vimentin as described before (17).
Immunohistochemistry for MMP-2 and MMP-9
Analysis of cultured cells. The fixed cells after culture were rehydrated with serial increasing dilutions of ethanol ending with two washes with PBS. Endogenous peroxidase activity was quenched by pretreatment with 0.3% hydrogen peroxide in PBS. Cells were then washed in PBS and incubated with 10% normal horse serum that served as a blocking agent for nonspecific binding. Antibodies to MMP-2 (Oncogene Research Products, Boston, MA) at a dilution of 1:200 and MMP-9 (Oncogene Research Products) at a dilution of 1:100 were applied and the cells were incubated at 4 C overnight. Cells were washed and incubated with biotinylated secondary antibody (Vector Laboratories, Inc., Burlingame, CA) for 60 min, washed again, and incubated with the avidin biotin-peroxidase complex (Vector Laboratories, Inc.) for another 60 min. After final washing, the immunoreactive proteins were visualized with the addition of 3,3'diaminobenzidine (Sigma) for 2–10 min. Cells were counterstained with hematoxylin, dehydrated in graded ethanol, cleared, and cover slips applied.
Analysis of placenta and fetal membrane tissues
Term (38- to 40-wk gestation) fetal membranes and placental villi (n = 5) were fixed by immersion in 4% paraformaldehyde and 0.2% glutaraldehyde in 70 mM phosphate buffer (pH 7.0) at 4 C overnight. Fixed tissues were then washed with PBS and stored in 90% ethanol before embedded in paraffin wax. The paraffin blocks were sectioned at 6 µm for immunohistochemistry (IHC). Tissue sections were deparaffinized in xylene, rehydrated, and washed in PBS. Staining was performed according to the same protocol described above. Control sections were treated in an identical manner with the omission of primary antibody.
Preparation of extracts of fetal membranes and placenta
One to two grams frozen fetal membranes or placenta tissue were homogenized on ice for 1 min in radioimmunoprecipitation assay lysis buffer [50 mM Tris-HCl (pH 7.5), 150 mM NaCl, 1% (wt/vol) sodium deoxycholate, 0.1% SDS, 100 µM sodium orthovanadate (Sigma), 1% (vol/vol) TritonX-100 (Fisher Chemicals, Fairlawn, NJ), and complete MiniEDTA-free protease inhibitors (Roche Molecular Biochemicals, Dorval, Canada)]. Homogenates were centrifuged at 4 C at 15,000 x g for 15 min, and supernatants were collected. Protein concentrations were determined by the Bradford assay (18). The extracts were stored at -20 C until further analysis.
Gelatin zymography
About 60 µg total protein of tissue extracts or 20 µl harvested culture medium was electrophoresed under nonreducing conditions in a 10% acrylamide gel containing 1 mg/ml gelatin (Difco Laboratories, Detroit, MI), according to the method of Fisher and Werb (19). After electrophoresis, the gels were washed at room temperature for 1 h in 2.5% Triton X-100, 50 mM Tris-HCl, pH 7.5 and then incubated at 37 C overnight in buffer containing 150 mM NaCl, 5 mM CaCl2, 50 mM Tris-HCl, pH 7.6. Thereafter, gels were stained with 0.1%(wt/vol) Coomassie brilliant blue R-250 in 30% (vol/vol) isopropyl alcohol, 10% glacial acetic acid for 60 min and destained in 10% (vol/vol) methanol, 5% (vol/vol) glacial acetic acid. Semiquantification of the bands corresponding to 72-kDa and 92-kDa gelatinases was performed with a densitometer.
Western blot
Protein samples of the tissue extracts (60 µg/lane) were loaded on a 10% (vol/vol) SDS-polyacrylamide gel under nonreducing conditions and transferred to a nitrocellulose membrane (20). Blots were washed with PBS-T (150 mM NaCl, 10 mM Na2HPO4, 1.5 mM NaH2PO4, and 0.1% Tween-20, pH 7.5) and incubated with blocking solution (5% skim milk powder in PBS-T) at 4 C overnight. Blots were then incubated with antibodies to MMP-2 and MMP-9 (Oncogene Research Products) at a dilution of 1:500 in blocking solution at room temperature for 1 h. The blots were rinsed five times for 5 min each time with PBS-T and incubated with secondary antiserum conjugated with horseradish peroxidase for 1 h (1:3000 dilution in blocking solution (Amersham Pharmacia Biotech). After appropriate washing, protein bands were detected by enhanced chemiluminescence (Amersham Pharmacia Biotech) and exposed to x-ray film (Eastman Kodak Co., Rochester, NY). The intensity of the protein signal was quantified using Duo Scan transparency Scanner and NIH Image 6.1 software.
Statistical analysis
Results are expressed as mean ± SEM for the number of different tissues (patients) studied. Differences between groups were examined using t test. Statistical significance was set at P < 0.05. Calculations were performed using SigmaStat (Jandel Scientific Software, San Rafael, CA).
Results
MMP-2 and MMP-9 production in human preterm labor and nonlabor fetal membrane
Extracts of both preterm labor and nonlabor human fetal membranes produced two major bands in zymograms. The molecular weights of the gelatinases suggested that they were MMP-2 (72 kDa) and MMP-9 (92 kDa) (Fig. 1A
). This was further confirmed by Western blot analysis using specific monoclonal antibodies (Fig. 2A). Both zymography and Western blot analysis showed significantly higher levels of MMP-9 in the tissue from laboring patients than from patients in the absence of labor (P < 0.01) (Fig. 1B, Fig. 2B). However, there was no significant difference of MMP-2 production in labor and nonlabor tissue extracts. The ratio of optical density of the two zymography bands (MMP-9:MMP-2) for all the samples was significantly greater in the labor group, compared with the nonlabor group (Fig. 1C).
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Extracts from term fetal membranes and placenta also produced MMP-2 and MMP-9 as primary products. The activity and output of MMP-9 was significantly higher in fetal membranes (Figs. 3 and 4) and placenta (Fig. 5) at labor (P < 0.01 and P < 0.05, respectively), compared with the nonlabor patients. However, there were no significant differences in MMP-2 levels between term labor and nonlabor tissue extracts. The ratio of optical density of the two zymography bands (MMP-9:MMP-2) in the term fetal membranes was significantly greater in the labor group than in the nonlabor group (P < 0.01) (Fig. 3C).
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To determine the cell types containing MMP protein, representative photomicrographs demonstrate the immunolocalization of MMP-2 and MMP-9 in term human fetal membranes (Fig. 6, a, c, and e) and placenta (Fig. 6, b, d, and f). MMP-2 was localized in some individual cells of the amnion mesenchyme, and strong staining was observed in the chorion laeve trophoblasts, decidual parietalis, and the vessels in placental villi. Faint staining was observed in amnion epithelium and placental syncytiotrophoblasts (Fig. 6, a and b). Strong staining for MMP-9 was noted in the amnion epithelium, chorion laeve trophoblasts, decidual parietalis, and placental syncytiotrophoblasts (Fig. 6, c and d). Omission of primary antibody eliminated staining in control sections (Fig. 6, e and f).
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To examine cellular production of MMPs further, we separated amnion epithelial and mesenchymal cells and generated relatively purified preparations of chorion and placental trophoblast cells. Separated amnion epithelial cells were more than 90% cytokeratin positive and vimentin negative, but the amnion mesenchymal cells were predominantly (>95%) vimentin positive and cytokeratin negative (17). The placental and chorion trophoblast preparations were predominantly cytokeratin positive (16). After 96 h of culture, these cells approached confluence and secreted MMPs. Zymography assay of the culture medium (Fig. 7a) and immunocytochemical analysis of the fixed cells (Fig. 7b) showed that placental syncytiotrophoblast cells produced MMP-9 but not MMP-2, whereas chorion trophoblast cells were able to secrete both MMP-2 and MMP-9. For amnion cell cultures, the epithelial cells produced only MMP-9, whereas the amnion mesenchymal cells produced only MMP-2 and very little MMP-9.
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In an attempt to define the cellular origins of MMP-2 and MMP-9 produced by human fetal membranes and placenta, we have used IHC and cell culture. MMP-9 was detected mainly in amnion epithelium, chorion laeve trophoblast, decidua parietalis, and syncytiotrophoblast from placental villi. This was consistent with the analysis of MMP-9 production in cell culture in vitro. Both immunocytochemical analysis of fixed cells and zymographic analysis of culture media showed that MMP-9 was produced mainly by the amnion epithelial cells, chorion trophoblast cells, and syncytiotrophoblasts. MMP-2 was detected in the chorion laeve trophoblasts and decidual parietalis; some individual cells of the amnion mesenchyme that lack MMP-9 showed positive MMP-2 staining. MMP-2 and MMP-9 were also distributed differently in placental villi. MMP-2 was found mainly around the vessels and there was faint staining in placental syncytiotrophoblasts. This difference was further confirmed by the analysis of cultured cells in vitro. MMP-2 was produced by amnion mesenchymal cells and chorion trophoblast cells, but amnion epithelial cells and syncytiotrophoblast cells did not secrete this enzyme. The cell-specific expression for MMP-2 and MMP-9 may be accounted for by the different matrix distribution in the tissues and the substrate difference for the two enzymes. Collagen I is the major component of the mesenchymal layer in fetal membranes and the stroma tissue in placental villi, and collagen Iv is localized mainly in the basement membrane (21, 22). Although both MMP-2 and MMP-9 degrade type Iv collagen, MMP-2 but not MMP-9 digests type I collagen (23). This characteristic may explain our finding that MMP-2 is distributed mainly in the stroma tissue and its associated cells, whereas MMP-9 is associated with epithelial cells.
Previous studies showed that MMP-9 activity in the fetal membranes increased markedly at the time of labor at term (11, 12). Our investigations indicate that not only term labor but also preterm labor is associated with a significant increase in the production of MMP-9 in human fetal membranes. This suggests that preterm and term labor may have a similar process of membrane rupture in which an increase in MMP-9 is an important step. The increase of MMP-9 results in the initiation of the full ECM degradation cascade, which leads to the rupture of the fetal membrane. Athayde et al. (24) reported that women with preterm premature rupture of membranes (PPROM) had significantly higher active MMP-9 concentrations in the amniotic fluid. We propose that this high level of MMP-9 may be accounted for by increased production of MMP-9 in the fetal membranes. No significant differences were observed for MMP-2 production between labor and nonlabor tissue extracts. However, it has been reported recently that active forms of MMP-2 in the amniotic fluid were decreased significantly in patients with spontaneous labor at term and with rupture of membranes, both term and preterm (13). The discrepancy between these results and our finding may suggest that the fetal membranes are not the only source for MMP-2 in amniotic fluid.
The results obtained in the present study also show clearly that term labor human placenta has a remarkably higher level of MMP-9 than that of term nonlabor placenta. This portion of MMP-9 likely comes mainly from the syncytiotrophoblasts in placental villi as suggested by our immunolocalization study. The increase in MMP-9 may facilitate placental separation from maternal tissues at labor. MMP-2 was also detected in placental tissue extracts; its level did not change between labor and nonlabor, as in the fetal membrane extracts. This differential regulation of MMP-2 and MMP-9 expression is consistent with MMP-2 as a constitutively expressed enzyme, whereas MMP-9 is considered inducible (25, 26). With the onset of labor, a number of hormones and cytokines (i.e. PG, TNF
, and IL-1) that have been implicated in the labor process may trigger the increase of MMP-9 levels in the fetal membranes and placenta (27, 28, 29). Thus, we propose that the labor-associated increase of MMP-9 in the fetal membranes and placenta may be because of its increased expression in cells of predominantly trophoblast lineage in response to these hormones, PGs, and cytokines such as TNF and IL-1.
The integrity of the extracellular matrix is essential for maintenance of fetal membrane function. An appropriate level of MMPs and their balance by inhibitors of MMP activity is needed for normal pregnancy. Overactivity of MMPs may contribute to PPROM. In this study, using zymography, we compared the MMP-2 and MMP-9 production in labor and nonlabor fetal membrane extracts from both preterm and term patients. Two major bands (MMP-2 and MMP-9) appeared in all samples, but the ratio of MMP-9:MMP-2 was significantly higher in both labor groups of patients. This ratio was unaffected by protein concentration and the volume of sample loaded. Several reports have shown that MMP-9 in amniotic fluid is increased significantly with labor (13, 24). The present study raises the possibility that the MMP-9: MMP-2 ratio in amniotic fluid may have value in relation to the incidence of PPROM and perhaps as a prediction marker of impending preterm labor.
Acknowledgments
Footnotes
Abbreviations: ECM, Extensive extracellular matrix; IHC, immunohistochemistry; MMP, matrix metalloproteinases; PPROM, preterm premature rupture of membranes.
Received June 28, 2001.
Accepted August 27, 2001.
References
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