Molecular Human Reproduction, Vol. 6, No. 3, 252-257,
March 2000
© 2000 European Society of Human Reproduction and Embryology
Uterine physiology |
CD9 is expressed on human endometrial epithelial cells in association with integrins 
6, 3 and ß1
1 Department of Gynecology and Obstetrics, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto, 606, 2 Institute for Virus Research, Kyoto University, 3 Institute for Frontier Medical Science, Kyoto University, Sakyo-ku, Kyoto 606-8507, and 4 Department of Gynecology and Obstetrics, Shinshu University School of Medicine, Asahi, Matsumoto 390-8621, Japan
Abstract
Recently we reported that CD9 is involved in the invasion of a trophoblast-like choriocarcinoma cell line, BeWo, probably through the regulation of integrin functions. Integrins have also been reported to be expressed in the human endometrium and it has been suggested that they play important roles in blastocyst implantation. This study used immunohistochemistry to investigate the expression of CD9 in the endometrium during the menstrual cycle. CD9 was found to be intensely expressed on the cell surface of the glandular epithelium throughout the menstrual cycle without any apparent differences in staining intensity. In addition, Western blotting analysis of the affinity-purified proteins confirmed that CD9 was associated with integrins ß1, 
3 and 6 in the human endometrium. Therefore it can be concluded that CD9, in association with integrins 6, 3 and ß1, is a constitutive molecule of the endometrial glandular epithelium. These results also suggest that CD9 may be an important regulator of these integrins in the human endometrium.
CD9/endometrium/integrin
Introduction
Blastocyst implantation is an important step in the establishment of pregnancy. Recently, it has been reported that integrins are expressed in the human endometrium as well as blastocyst and it is suggested that they may play important roles in blastocyst implantation (Campbell et al., 1995
; Tabibzadeh and Babaknia, 1995). In the endometrium, integrin 1ß1, 4ß1 and vß3 were found to be expressed on epithelial cells during the putative implantation window (Lessey et al., 1994). Clinically, lack of vß3 during the implantation window has been reported in patients with unexplained infertility (Lessey et al., 1995). Integrin ß1 subunits have been predominantly detected on human endometrial stromal cells in the secretory phase and are maintained at high levels in the decidua (Shiokawa et al., 1996a). Furthermore, the outgrowth of mouse embryos on human decidual cells was inhibited by the addition of a monoclonal antibody against integrin ß1, implying the involvement of this integrin in blastocyst implantation (Shiokawa et al., 1996b).
Other studies have found that integrin ß1 is also expressed on luminar and glandular epithelial cells of the human endometrium and that its expression is constitutive throughout the menstrual cycle (Lessey et al., 1992; Tabibzadeh, 1992). However, the physiological role of integrin ß1 on epithelial cells remains to be clarified.
The activation and inactivation of integrin has been demonstrated in a variety of cells, and it has been suggested that some molecules can modulate integrin activities (Leng et al., 1998; Martin-Bermudo et al., 1998). Recently, we reported that CD9 expressed on the extravillous trophoblasts of the human placenta is associated with integrin 3ß1 and 5ß1 and granulosa cells of the human ovary with integrin 6ß1 (Hirano et al., 1999a; Takao et al., 1999). We have also shown that CD9 is implicated in the function of integrins on the invasive property of the human trophoblast-like choriocarcinoma cell line, BeWo (Hirano et al., 1999b), which suggests that CD9 may be an important regulator of integrin functions.
In the present study, therefore, we examined immunohistochemically whether CD9 is expressed in the human endometrium during the menstrual cycle. We also examined the association of CD9 with the integrin ß1 family by Western blotting using immunoaffinity-purified proteins, in order to investigate whether CD9 is functionally related to integrins in the human endometrium.
Materials and methods
Tissues
Human endometrial tissues were obtained from women with normal menstrual cycles, who had undergone hysterectomy for the treatment of uterine myoma, but none of whom were receiving any type of hormonal or drug therapy. Each endometrial specimen was examined histologically and dated according to the criteria of Noyes (Noyes et al., 1950). Of the 22 normal endometrial tissues, 10 were found to be in the proliferative phase and 12 in the secretory phase. This study was approved by the ethical committee at Kyoto University, Japan, and pre-operative informed consent was obtained from each patient.
Antibodies
The mouse anti-human CD9 monoclonal antibody (mAb), TP-82 [immunoglobulin G1 (IgG1) class] was purchased from Nichirei Co (Tokyo, Japan). An anti-human CD9 mAb, SYB-1 (IgG1 class) was a generous gift from Dr C.Boucheix and Dr E.Rubinstein, INSERM U268, Hôpital Paul Brousse, France (Boucheix et al., 1983). An unrelated mouse anti-trinitrophenyl (anti-TNP) mAb (IgG1 class) was used as the negative control (Tsujimura et al, 1990). The mouse anti-human integrin 3 mAb 11G5 (IgG1 class) was purchased from Serotec (Oxford, UK), and the mouse anti-human integrin 6 mAb OG-1 (IgG1 class) was raised in our laboratory (Fujiwara et al., 1993, 1997; Honda et al., 1995). The mouse anti-human integrin ß1 mAb DF5 (IgG1 class) was purchased from Affinity Research Products Ltd (Nottingham, UK).
Fluorescein isothiocynate (FITC)-conjugated rabbit anti-mouse immunoglobulins and FITC-conjugated goat anti-rat immunoglobulins were purchased from Dako (Glostrup, Denmark) and were used as the second antibodies in the histochemical analysis. Horseradish peroxidase (HRP)-conjugated rabbit anti-mouse immunoglobulins (Dakopatts; Dako) was used as the second antibody in Western blotting.
Indirect immunofluorescence staining
Immunohistochemical analysis was performed as described elsewhere (Fujiwara et al., 1993) with minor modifications. Individual specimens were embedded in OCT compound (Tissue-Tec, Miles Scientific, Naperville, IL, USA), snap-frozen in liquid nitrogen and stored at –80°C. The frozen tissues were then sliced to a thickness of 7 µm using a cryostat microtome (Cryocut 1800; Reichert-Jung, Heidelberg, Germany), immediately air-dried on Neoplene (Nisshin EM, Tokyo, Japan)-coated glass slides and fixed in acetone at –20°C for 5 min. The slides were either examined immediately or stored at –20°C until use. They were incubated with anti-CD9 mAb, TP-82 (5 mg/ml) or the anti-TNP mAb (5 mg/ml), for 30 min at room temperature. They were washed in phosphate-buffered saline (PBS), and then incubated with FITC-conjugated second antibody (diluted 1:40) for 30 min at room temperature in the dark. Finally the slides were washed, mounted with Perma Fluor Aqueous Mounting Medium (Immunon, Pittsburgh, PA, USA), which reduces fluorescent fading, and examined under a fluorescence microscope (Nikon, Tokyo, Japan).
Western blot analysis
Endometrial tissues in the secretory phase (0.2 g, wet tissue) were lysed in sample buffer [2 ml, 20 mmol/l Tris–HCl pH 8.6, 1% sodium dodecyl sulphate (SDS), 20% glycerol, BPB] containing p-amidinophenylmethanesulphonylfluoride hydrochloride (1 mmol/l; Wako Pure Chemicals, Osaka, Japan), leupeptin (20 mg/ml; Peptide Institute, Osaka, Japan), and pepstatin (20 mg/ml; Peptide Institute), separated by 12% SDS–polyacrylamide gel electrophoresis (PAGE) under non-reducing conditions, and electrically transferred onto a polyvinylidene difluoride (PVDF) membrane (Millipore Corporation, Bedford, MA, USA) in a buffer containing 25 mmol/l Tris–HCl, 192 mmol/l glycine and 20% methanol. The filter membranes for immunostaining were blocked with a blocking agent (Block Ace; Snow Brand, Tokyo, Japan). After blocking, the membranes were washed in PBS three times and incubated with mAb solution [diluted ascites 1:1400 in PBS containing 0.1% bovine serum albumin (BSA) for SYB-1, 0.2 mg/ml in PBS containing 0.1% BSA for anti-TNP mAb, and 0.2 mg/ml in PBS containing 0.1% BSA for DF5, anti-integrin ß1 mAb] for 2 h at room temperature. The membranes were washed several times with PBS, and incubated for 1 h with HRP-conjugated rabbit anti-mouse IgG antibody (diluted 1:500 in PBS containing 0.1% BSA). After several washes, the binding of the antibodies was visualized by incubation with 0.2 mg/ml of 3,3'- diaminobenzidine tetrahydrochloride and 0.006% H2O2 in PBS.
Western blotting and silver staining of the affinity purified proteins from the endometrium
Endometrial tissue in the secretory phase (4 days after ovulation; 0.5 g, wet weight) was homogenized in 5 ml of 40 mmol/l phosphate buffer, pH 7.3, containing 150 mmol/l NaCl, 1 mmol/l CaCl2, 1 mmol/l MgCl2, 1% CHAPS (Wako Pure Chemicals) and protease inhibitors including p-amidinophenylmethanesulphonylfluoride hydrochloride (0.25 mg/ml), 10 mg/ml leupeptin (Peptide Institute), and 10 mg/ml pepstatin (Peptide Institute). After centrifugation at 9000 g for 30 min, the concentration of CHAPS in the lysate was reduced by dilution to 0.3%. The lysate was passed through a column containing 10 ml of anti-TNP-conjugated Affigel 10 (2 mg IgG/ml gel; Bio-Rad Laboratories, Hercules, CA, USA) at 4°C to remove non-specifically bound compounds. The through-pass fractions were incubated with 0.2 ml of anti-CD9 (TP-82, 100 mg IgG/ml gel), anti-integrin 3 (11G5, 100 mg IgG/ml gel) or anti-integrin -6 conjugated Affigel 10 (OG-1, 200 mg IgG/ml gel) at 4°C for 2 h. After thorough washing of the gels, the purified antigens and their associated proteins were eluted with sample buffer. They were transferred after 12% SDS–PAGE (non-reduced conditions) onto a PVDF membrane. The membranes were stained with anti-CD9 mAb (SYB-1), the anti-integrin ß1 mAb (DF5), and the control mAb (anti-TNP) as described above. In some experiments, the separated proteins by means of 12% SDS–PAGE were stained with a silver stain kit (Wako Pure Chemicals).
Results
Immunohistochemical analysis of CD9 expression in human endometrium
In the normal endometrium during both the proliferative and secretory phases, the CD9 antigen was detected at high intensity on the cell surface of luminar and glandular epithelial cells. Almost all stromal cells were negative for CD9 expression throughout the menstrual cycle, although focally or sporadically CD9 positive cells were seen around a few glands. There were no significant differences in the expression intensity of CD9 on epithelial cells between the proliferative and secretory phases (Figure 1). The immunohisochemical profiles for CD9 expression in the human endometrium are summarized in Table I.
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Western blot analysis of CD9 protein expression in endometrial tissues
The expression of CD9 protein in the human endometrium was also confirmed by Western blot analysis. The molecular mass of CD9 in the normal endometrium detected by SYB-1 was 26.5 kDa, which is compatible with that previously reported (Kersey et al., 1981
) (Figure 2, lane 1). Integrin ß1 was detected by DF5 mAb as a single band at 110 kDa, which is also compatible with the molecular mass, reported elsewhere (Figure 2, lane 2).
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Silver staining of the proteins that were purified from the endometrium using anti-CD 9, anti-integrin
3 and anti-integrin 6 mAbsThe protein bands that were affinity-purified with mAbs from the endometrium were entirely different from those of the lysate before purification (Figure 3
, lane 7). The proteins purified with anti-CD9 mAb (TP-82) were detected as specific bands at 145, 110–115, 57, 46 and 26.5 kDa (Figure 3, lane 3). The proteins purified with 11G5 and OG-1 mAbs were detected as specific bands at 145, 110–115 and 26.5 kDa respectively (Figure 3, lanes 1 and 2). The main bands, 145 kDa, correspond to the reported molecular mass of integrin 3 and 6 in non-reducing conditions. The other common bands at 110–115 and 26.5 were considered to be integrin ß1 and CD9 as shown in the Western blot analysis using the whole lysate of endometrial tissue (Figure 2
), which was further confirmed by the following Western blot analysis.
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Western blot analysis demonstrating the association of CD9 molecule with integrins
3, 6 and ß1By Western blot analysis of the proteins purified from the endometrial tissues by anti-CD9 mAb (TP-82), integrin ß1 was detected as a protein band at 110 kDa (Figure 4
, lane 4). In the proteins purified with anti-integrin 3 (11G5) and a6 (OG-1) mAbs, CD9 was clearly detected as a protein band at 26.5 kDa (Figure 4, lanes 2 and 3), indicating that these integrins were associated with CD9. Two bands detected at 57 and 46 kDa in the proteins purified with CD9 mAb (TP-82) remain to be identified.
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Discussion
The CD9 molecule is a 24–27 kDa glycoprotein, which was originally reported to be expressed on the cell surface of haematopoietic cells such as pre-B-lymphocytes, platelets, and activated T-lymphocytes (Kersey et al., 1981; Boucheix et al., 1983). CD9 is a member of the tetraspan family of four transmembrane domain-containing proteins, a family which includes other leucocyte antigens such as CD37, CD53, CD63, CD81, and CD82 (Rubinstein et al., 1996). Several studies have demonstrated that the CD9 molecule is involved in haematopoietic cell functions, e.g. platelet activation, aggregation and adhesion, neutrophil adhesion and pre-B cell adhesion (Jennings et al., 1990; Masselis-Smith et al., 1990; Forsyth, 1991). It has also been reported that the CD9 molecule is involved in Schwann cell migration and adhesion (Hadjiargyrou and Patterson, 1995).
This study demonstrated that CD9 was strongly expressed along the cell membrane of the endometrial epithelium in the proliferative phase as well as in the luteal phase of the menstrual cycle. No cyclic changes in staining intensity were observed during the menstrual cycle. In addition, CD9 was rarely expressed in the stromal cells of the endometrium. These results imply that CD9 is a constitutive element of the human endometrial epithelium, which is not affected by hormonal changes during the menstrual cycle.
As well as other tetraspan family molecules, CD9 has been reported to be associated with integrins and to play an important role in the adhesion and motility of cells (Rubinstein et al., 1994). An association of CD9 with ß1-related integrins, e.g. integrin 3ß1 (Nakamura et al., 1995), 4ß1 (Rubinstein et al., 1994), or 6ß1 (Schmidt et al., 1996), has been demonstrated on the cell surface of several cells. In the reproductive system, CD9 expressed in extravillous trophoblasts of the human placenta has been reported to be associated with integrin 3ß1 and 5ß1 and granulosa cells of human ovary with integrin 6ß1 (Hirano et al., 1999a; Takao et al., 1999). The present study revealed, by means of Western blot analysis of the affinity-purified proteins, that integrin 3ß1 and 6ß1 are also associated with CD9 in the human endometrium. We immunohistochemically observed the constitutive expression of integrins 3, 6 and ß1 on the epithelial cells in the human endometrium, as reported previously (Lessey et al., 1992; Tabibzadeh, 1992) (data not shown).
Although the ligands or mediators for CD9 molecules have not been found, there is evidence to suggest that morphological or functional alteration of the CD9 molecule by anti-CD9 mAbs can lead to significant biological changes in various cells (Jennings et al., 1990; Masselis-Smith et al., 1990; Forsyth, 1991; Hadjiargyrou and Patterson, 1995). Using anti-CD9 mAb, we previously demonstrated that CD9 regulates the invasion of BeWo cells. Furthermore, we showed that integrin ß1 is deeply involved in this regulatory effect of CD9 on BeWo cell invasion, suggesting that CD9 is one of the candidates that activate or inactivate integrin functions (Hirano et al., 1999b). The regulation of integrin function in the luminar surface epithelial cells is considered to be important for adhesion of blastocyst, which is an essential step in embryo implantation. Although the precise role of CD9 in the human endometrium remains to be clarified, the constitutive expression of CD9 suggests that this molecule may have a physiological role, possibly in the process of implantation in human endometrium.
Recently, heparin-binding epidermal growth factor (EGF), a member of the EGF family of growth factors, was reported to be associated with CD9 and to require co-expression of CD9 for its optimal activity (Nakamura et al., 1995; Lagaudriere-Gesbert et al., 1997). In the human endometrium, heparin-binding EGF mRNA has been reported to be expressed throughout the menstrual cycle (Birdsall et al., 1996). In rodents, it was found that heparin-binding EGF-like growth factor, which is synthesized exclusively in the luminar epithelium at the site of blastocyst apposition, may be a mediator in the process of implantation (Das et al., 1994; Raab et al., 1996). These findings clearly show the need for further investigation of the role of CD9 in the process of blastocyst implantation in the human endometrium.
In conclusion, the CD9 molecule was found to be constitutively expressed on the luminar and the glandular epithelium throughout the menstrual cycle. The association of CD9 with integrins 3, 6, and ß1 in the human endometrium suggests that CD9 may have an endometrial function in association with these integrins.
Notes
5 To whom correspondence should be addressed 
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