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1 State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100080, China and 2 Department of Pathology, University of Oulu and Oulu University Hospital, FI-90014 Oulu, Finland
Correspondence should be addressed to Yan-ling Wang or Yun-shang Piao, State Key Laboratory of Reproductive Biology, Institute 15 of Zoology, Chinese Academy of Sciences, 25 Bei Si Huan Xi Road, Beijing 100080, China; Email: wangyl{at}ioz.ac.cn or piaoys{at}ioz.ac.cn
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionAcknowledgementsReferences |
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The process of trophoblast cell invasion is associated with the degradation of extracellular matrix (ECM) proteins mainly by the action of matrix metalloproteinases (MMPs), a family of zinc-dependent proteolytic enzymes. So far, more than 20 isoforms of MMPs have been identified. Based on the substrate specificities, MMPs can be classified into four groups: gelatinases, collagenases, stromelysins and membrane-type MMPs (MT-MMPs) (Woessner & Nagase 2000). Gelatinases A and B, which are also called MMP-2 and MMP-9 respectively, mainly degrade collagen IV (Col IV) and a number of other ECM proteins, such as Col I, V, VII, IX and X, fibronectin (FN), laminin (LN), elastin and vitronectin (Woessner & Nagase 2000). MT-MMPs contain six members, the best characterized of which is MT1-MMP, also called MMP-14 (Ohuchi et al. 1997). It has been shown that MMP-14 functions not only as an activator for some MMPs, such as MMP-2 and MMP-13 (Strongin et al. 1995, Knauper et al. 1996), but also as a proteolytic enzyme degrading FN, LN, Col I and Col III (D’Ortho et al. 1997, Ohuchi et al. 1997).
Under physiologic conditions, the MMP activities are tightly regulated by the tissue inhibitors of MMPs (TIMPs), four of which have been described (Woessner & Nagase 2000). Each of them preferentially targets different MMPs, although each of the four types of TIMPs also has a lower inhibitory effect on other MMPs (Woessner & Nagase 2000).
In the past, great efforts have been made to understand the involvement of MMPs and TIMPs in pregnancy. Accumulating data suggest that MMP-9 may play a more important role than MMP-2 during pregnancy (Librach et al. 1991, 1994, Polette et al. 1994, Shimonovitz et al. 1994, Hurskainen et al. 1996, Xu et al. 2000). The expression of MT1-MMP has also been found in human placenta during the first trimester (Nawrocki et al. 1996, Hurskainen et al. 1998, Xu et al. 2000, 2001). Meanwhile, the results of a number of studies have indicated that TIMP-1, -2, and -3 may play critical roles in regulating the invasion of trophoblast cells during embryo implantation (Librach et al. 1991, Polette et al. 1994, Bass et al. 1997). However, the roles of various MMPs and TIMPs in early implantation are not clearly determined, mostly because of the restriction of study materials.
Tubal pregnancy is a form of abnormal pregnancy in which the embryo implants in the fallopian tube rather than in the uterus. However, the fetomaternal compartment removed from tubal pregnant patients often possesses an integrated fetomaternal interface, as shown in our recent studies (Li et al. 2003, Qin et al. 2003a). Moreover, tubal pregnancy triggers normal immunoreactivity and hormonal activation of the maternal body (Earl et al. 1986, Randall et al. 1987, Marx et al. 1999), as well as giving rise to immunologically normal and hormonally active trophoblast cells (Vassiliadou & Bulmer 1998, Li et al. 2003, Qin et al. 2003a). Therefore, tubal pregnancy may provide a unique model to study the mechanism of implantation, particularly from the aspect of trophoblast cells.
In the present study, the localization of MMP-2, -9 and -14, as well as TIMP-1, -2 and -3, at the fetomaternal interface has been investigated in human specimens collected from gestational weeks 3–9 of tubal pregnancy by immunohistochemistry (IHC) and in situ hybridization (ISH).
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Materials and Methods |
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IHC
IHC assay was performed as previously described (Qin et al. 2003a). Paraffin sections were deparaffinized and rehydrated in a descending ethanol series. If required, as indicated in Table 1
, antigen retrieval was performed in 10 mM citrate buffer (pH 6.0) at 95 °C for 15 min. After treatment with 1% hydrogen peroxide to eliminate endogenous peroxidase activity, the sections were incubated at 4 °C overnight with unique primary antibody diluted in Tris hydrochloride buffer (TBS) containing 1% bovine serum albumin (BSA). The antibodies and the working concentration used are summarized in Table 1. Normal rabbit immunoglobulin (Ig) G and normal mouse IgG were used as negative control for the polyclonal and monoclonal antibodies respectively. Final visualization was achieved with the Envision System (DAKO, Carpinteria, CA, USA), according to the manufacturer’s instructions. Counterstaining with hematoxylin was performed before mounting the slides. All results are based on the evaluation of three blinded observers.
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ISH was performed as previously described (Qin et al. 2003a). In brief, paraffin sections were routinely deparaffinized and rehydrated. Digestion with 4 µg/ml proteinase K (Gibco, Carlsbad, California) was performed after treatment with 0.2 M HCl and denaturing at 70 °C in 2 xSSC. Post-fixation was performed in 4% PFA at room temperature, followed by incubation in PBS containing 0.1% active DEPC (Fluka, Buchs SG, Switzerland). The slides were then prehybridized for 4 h at 58 °C in prehybridization buffer (50% formamide, 20 mM Tris–HCl, 50 mM EDTA, E. coli tRNA 0.5 mg/ml and DTT 100 mM) and further hybridized for 18 h at 58 °C in fresh hybridization buffer containing 1 ng/µl probes. After washing in consecutive baths of 2 xSSC and 0.1 xSSC, slides were blocked with 0.5% blocking reagent (Boehringer Mannheim, Mannheim, Germany) and then incubated with alkaline phosphatase-coupled anti-DIG antibody (dilution 1:500). Color development was in buffer II (100 mM Tris–HCl, 100 mM NaCl and 50 mM MgCl2, pH 9.5) containing 4.5 µl NBT and 3.5 µl BCIP (Boehringer Mannheim). Nonspecific staining was removed by rinsing with 95% EtOH. Slides were mounted in resin after dehydration with EtOH and xylene. The results were assessed based on the blinded evaluation of three observers.
Reproducibility of the result
At least three representative cases were included at each gestational stage, and all the IHC and ISH experiments were repeated at least three times.
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). Villous cytotrophoblast (VCT) cells also exhibited strong MMP-2 expression (Fig. 1B, C, F and G). MMP-2 was absent from some syncytiotrophoblast (ST) cells (Fig. 1B and F), but present in ST cells of a portion of the villi with the immunoreactivity accentuating to the apical border of the syncytial layer (Fig. 1C and G). Meanwhile, intensive MMP-2 signal was found in perivascular EVCT (PEVCT) cells penetrating the maternal vessels (Fig. 1D and H). The results of ISH and IHC were almost parallel to each other, except that no immunoreactive MMP-2 could be detected in villous mesenchymal (M) cells (Fig. 1F and G) that showed positive signal as revealed by ISH (Fig. 1B and C). MMP-9 was widely expressed by extra-villous trophoblast cells, including CCT, EVCT invading maternal interstitium and PEVCT cells (Fig. 1I, L, M and P). Expression of MMP-9 in floating villi was similar to that of MMP-2, as detected by both ISH (Fig. 1J and K) and IHC (Fig. 1N and O). MMP-14 was present in EVCT and PEVCT cells, but not in approximal CCT cells (Fig. 1Q, S, T and W). Along the invasive pathway, the intensity of MMP-14 increased from distal CCT to EVCT cells deeply invading maternal tissue (Fig. 1Q and T). MMP-14 was also found in VCT, ST and some villous mesenchyma cells in varying abundance (Fig. 1U and V). In the syncytial layer, MMP-14 immunoreactivity at the apical border appeared to be stronger than that in other areas (Fig. 1U and V). However, the mRNA signal of MMP-14 was barely detected in ST cells (Fig. 1R).
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Expression pattern of TIMP-1, -2 and -3 at feto–maternal interface of tubal pregnancy during gestational weeks 3–9
IHC and ISH were performed to examine the presence of TIMP-1, -2 and -3 at the feto–maternal interface. TIMP-1 could be detected in CCT, invading EVCT and PEVCT cells (Fig. 2A and B). Along the invasive pathway, the signal intensity of TIMP-1 increased gradually from CCT cells to EVCT cells that had invaded the maternal interstitium (Fig. 2A). The PEVCT cells also strongly expressed TIMP-1 (Fig. 2B).
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). The spatial expression pattern of TIMP-2 in trophoblast cells was very similar to that of TIMP-1 (Fig. 2D–F). In a portion of villi, TIMP-2 signal was concentrated at the apical border of the syncytium (Fig. 2F). TIMP-3 was detected in CCT, EVCT, PEVCT, VCT and M cells, and the intensity did not change significantly (Fig. 2G–I). However, villous ST cells showed no expression of TIMP-3 (Fig. 2I). On the maternal side, TIMP-1, -2 and -3 were strongly expressed in fallopian epithelial cells, but weakly in stromal cells (data not shown).
Expression pattern of MMP-2, -9 and -14 and TIMP-1, -2 and -3 in placental villi of normal pregnancy during the first trimester
Immunoreactivity of MMP-2, -9 and -14 and TIMP-1, -2 and -3 was detected in placenta villi of the normal intrauterine pregnancy at gestational weeks 7–8. The distribution patterns of these proteins in VCT and proximal CCT cells in normal pregnancy were almost the same as that in tubal pregnancy (Fig. 3A–M).
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). Their expression levels were increased at weeks 5–7 (Fig. 4B, E and K) and peaked at weeks 8–9 (Fig. 4C, I and L). However, the abundance of TIMP-2 mRNA appeared to decrease as gestational age increased (Fig. 4G–I). The results of IHC indicated that the dynamic temporal changes in the expression of MMP-9 and TIMP-1, -2 and -3 in EVCT cells were identical to those revealed by ISH (data not shown).
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Discussion |
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It has been shown that the uterine CD56+leukocytes comprising up to 50% of the immunocompetent cells in maternal decidua are absent from tubal implantation sites where stromal cells do not decidualize (Marx et al. 1999). Both the decidua and leukocytes have been postulated to play roles in the modulation of cytotrophoblast invasion. Therefore, it is likely that the lack of decidua and deciduaassociated leukocytes in the tubal implantation site affects the expression of MMPs and TIMPs in trophoblast cells. It has also been shown that in tubal pregnancy, the trophoblast appears to be somewhat overinvasive (Neratzoula & Judith 1998). Therefore, the strong expression of MMPs and TIMPs in the invasive EVCT cells of tubal pregnancy described in this study might be a reflection of this overinvasive phenotype. However, we also found that the expression patterns of these molecules in VCT and proximal CCT cells were significantly similar between tubal and normal pregnancy. The expression manners of these molecules in the invasive EVCT cells were not compared because of the unavailability of the intact feto–maternal interface in normal intrauterine implantation. Recently, Qin et al. (2003a) revealed the switching of ECM and corresponding integrin receptors in trophoblast cells along the invasive pathway in fallopian implantation, and suggested the existence of balanced regulation of trophoblast invasion in tubal pregnancy. Previously, Randall et al.(1987) had demonstrated that the early development of the placenta, as well as invasion of the placental bed and tubal vessels by EVCT cells, occurred in the tube in exactly the same way as in the uterine endometrium and spiral arteries. They also suggested that the ability of the blastocyst to implant in the tube, with subsequent normal placentation, might indicate that these processes are purely a function of trophoblastic tissue, with maternal tissues playing only a passive role. However, this hypothesis is not yet confirmed. On the other hand, there are reports in the literature of a strong expression of TIMP-1, -2 and -3 in maternal decidual cells during normal intrauterine pregnancy (Polette et al. 1994, Hurskainen et al. 1996). This is one of the mechanisms to prevent overinvasion by trophoblast cells of maternal tissue. However, fallopian tissues express low levels of TIMPs during tubal pregnancy, as observed in this study (data not shown). Therefore, inhibition of trophoblast invasion by maternal tissue has been largely reduced or even lost during fallopian implantation. This may be one reason that the fallopian tube is always broken when embryo implantation occurs there.
As mentioned above, specimens with feto–maternal interface at gestational weeks 3–4 are rarely available from normal pregnancies, although they can be easily obtained from tubal pregnancy. In this study, it appears that the expression of MMP-9 and TIMP-1, -2, and -3 in invasive EVCT cells is gestational age-dependent. We have previously demonstrated a similar change pattern of MMP-9 and TIMP-1 expression in cultured human cytotrophoblast cells during weeks 6–11 of normal pregnancy (Xu et al. 2000). Our recent study showed that the expression of integrins 
1, ß1 and 5ß1 and their corresponding ECM ligands (that is, LN and FN) went up gradually during weeks 3–7, and then slightly declined by weeks 8–9 (Qin et al. 2003a). LN and FN have been shown to promote the migration of cultured human cytotrophoblast cells with the induced expression of MMP-9 and TIMP-1 and TIMP-3 (Xu et al. 2001). These data show that various MMPs/TIMPs function in trophoblast cells at different gestational stages. It seems that MMP-2 and -14 and TIMP-2 play major roles in the invasion by trophoblasts of maternal tissue at the early implantation stage. Later, the increased LN and FN, as well as the corresponding integrin receptors in trophoblast cells, may regulate the production of MMP-9 and TIMP-1 and -3 to promote trophoblast invasion.
The spatial expression pattern of MMPs/TIMPs in trophoblast cells at the intact fetomaternal interface during early implantation was also determined in the present study. The presence of MMP-14 and TIMP-1 and -2 was poorly observed in proximal CCT cells, but could be detected increasingly from the distal CCT cells to the invading EVCT cells, while MMP-9 and TIMP-3 were constitutively expressed in trophoblast cells along the invasive pathway. This suggests that trophoblast cells at various differentiation stages may possess different abilities to degrade the ECM proteins, and that the balance among various MMPs and TIMPs plays a critical role in ECM degradation. Recently, we found the ascending expression of integrins 1ß1 and 5ß1 and corresponding ECM ligands (LN and FN) along the invasive pathway in both tubal pregnancy and normal pregnancies of the rhesus monkey (Qin et al. 2003a,b). Together with the data of Damsky et al.(1992, 1994) and Xu et al.(2001), these observations imply the existence of concerted autocrine pathways, which may regulate the spatial change of MMPs/TIMPs and ECMs/integrins, and thereby determine the controlled invasion of trophoblasts.
During normal implantation, the remodeling of uterine spiral arteries mediated by trophoblast cells is an essential event for successful pregnancy (Popek 1999). During fallo-pian implantation, invasion of the maternal blood vessels by EVCT cells also occurs, although the tubal mucosa lacks spiral arteries (Randall et al. 1987). Investigations performed in rhesus monkeys showed that during implantation, MMP-2 and -9 are present in EVCT cells within the spiral artery lumen and wall (Blankenship & King 1994, Blankenship & Enders 1997). In the present study, we observed that the mucosa blood vessels were densely surrounded by PEVCT cells; morphologically, the vascular destruction is probably caused by direct penetration of PEVCT cells into the lumen through the artery wall. Accordingly, our data demonstrated that these PEVCT cells possess significant amounts of both MMP-2 and -9 to ensure their invasive ability. In the present study, MMP-2 was mainly localized in PEVCT cells among the various invasive EVCT cells, indicating that this protease may play a unique role in vascular remodeling. Meanwhile, the role of MMP-9 and MMP-14 during this process cannot be excluded due to their strong expression in PEVCT cells. The distribution of various TIMP molecules further indicates the controlled invasion and remodeling of maternal blood vessels by trophoblast cells. On the other hand, MMP-2 was barely detected in the EVCT cells that invaded the vessel lumen, whereas MMP-9 remained (data not shown). This result differs from the observation that MMP-2 exists in the EVCT cells that invaded the spiral artery lumen in the rhesus monkey. The EVCT cells that invaded the vascular lumen of the fallopian mucosa may have different features and potentials from the intraluminal EVCT cells penetrating the spiral artery walls during intrauterine pregnancy. The difference may result from the different environments of the fallopian blood vessel and the endometrial spiral artery.
During early implantation, the placental villi undergo dramatic development, involving villous tissue remodeling. The present study showed that MMP-2, -9 and -14, as well as TIMP-1, -2 and -3, are produced by VCT cells during tubal pregnancy, in agreement with the results from the studies of normal pregnancy, as shown in this study and elsewhere (Hurskainen et al. 1996, 1998, Bass et al. 1997). As MMP-2 and -9 are the main proteases participating in the degradation of the basement membranes, their coexpression with MMP-14, TIMP-2 and -3 may coordinate the reconstruction of the basement membranes beneath the trophoblast epithelium during villous development. In villous mesenchymal cells, MMP-9 and -14, as well as TIMP-1, -2 and -3, both proteins and mRNAs, could be detected.
However, mRNA, but not protein, of MMP-2 was found in villous mesenchymal cells during tubal pregnancy, as shown in this study and reported in normal pregnancy (Hurskainen et al. 1996). Hence, both MMP-9 and -14, which are subject to modulation by TIMP-2 and -3, are likely to play an important role in ECM degradation during placentation.
One interesting observation was that immunoreactivities of MMP-2 and -14 and TIMP-2 could always be found in the apical border of the villous syncytial layer. ST cells are a group of highly differentiated cells that contact maternal blood directly, and they are the main sources of various placental endocrine/paracrine factors. It has been demonstrated that TIMP-2 is required for the MMP-14-mediated activation of MMP-2 (Kinoh et al. 1996, Okada et al. 1997, Wang et al. 2000). Their colocalization in the apical border of ST cells is probably the indication of the MMP-2 activation in these cells, as well as the participation of the enzymes in processing of paracrine factors synthesized by these active ST cells. On the other hand, we found that the proportion of MMP-2-positive ST cells was much higher at weeks 3–4 in tubal pregnancy. Until weeks 8–9, MMP-2 signal was rarely detected in ST cells (data not shown). It is believed that ST cells first adhere to maternal endometrium during the very early stage of implantation. Puistola et al.(1989) pointed out the ability of the preimplantation embryo to produce MMP-2. Hence, the high level of MMP-2 in ST cells during the early implantation stage also suggests that MMP-2 may play the predominant role in the initiation of implantation.
In summary, this study clarifies the temporal and spatial expression pattern of various MMPs and TIMPs at the human fetomaternal interface, especially at the very early stage of pregnancy, by using tubal pregnancy as a unique model.
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Footnotes |
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionAcknowledgementsReferences |
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Y.-l. Wang, W. Qiu, H.-c. Feng, Y.-x. Li, L.-z. Zhuang, Z. Wang, Y. Liu, J.-q. Zhou, D.-h. Zhang, and G. S.W. Tsao Immortalization of normal human cytotrophoblast cells by reconstitution of telomeric reverse transcriptase activity Mol. Hum. Reprod., July 1, 2006; 12(7): 451 - 460. [Abstract] [Full Text] [PDF]
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J. M. Corpa Ectopic pregnancy in animals and humans. Reproduction, April 1, 2006; 131(4): 631 - 640. [Abstract] [Full Text] [PDF]
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 B. E. Seeber and K. T. Barnhart Suspected Ectopic Pregnancy Obstet. Gynecol., February 1, 2006; 107(2): 399 - 413. [Abstract] [Full Text] [PDF]
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 R. L. Jones, J. K. Findlay, P. G. Farnworth, D. M. Robertson, E. Wallace, and L. A. Salamonsen Activin A and Inhibin A Differentially Regulate Human Uterine Matrix Metalloproteinases: Potential Interactions during Decidualization and Trophoblast Invasion Endocrinology, February 1, 2006; 147(2): 724 - 732. [Abstract] [Full Text] [PDF]
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 S. Goldman and E. Shalev Difference in Progesterone-Receptor Isoforms Ratio Between Early and Late First-Trimester Human Trophoblast Is Associated with Differential Cell Invasion and Matrix Metalloproteinase 2 Expression Biol Reprod, January 1, 2006; 74(1): 13 - 22. [Abstract] [Full Text] [PDF]
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W. Qiu, S.-X. Bai, M.-r. Zhao, X.-q. Wu, Y.-G. Zhao, Q.-X. A. Sang, and Y.-L. Wang Spatio-Temporal Expression of Matrix Metalloproteinase-26 in Human Placental Trophoblasts and Fetal Red Cells During Normal Placentation Biol Reprod, April 1, 2005; 72(4): 954 - 959. [Abstract] [Full Text] [PDF]
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