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Original Studies |
Department of Obstetrics and Gynecology, C. S. Mott Center for Human Growth and Development (R.E.L., R.K., R.R., D.R.A.), and Departments of Pathology (N.D.R.) and Anatomy and Cell Biology (D.R.A.), Wayne State University, Detroit, Michigan 48201-1415; and the Departments of Obstetrics and Gynecology and Molecular and Integrative Physiology, Ralph L. Smith Research Center, University of Kansas Medical Center (S.K.De., J.W., S.K.Da.), Kansas City, Kansas 66160-7336
Address all correspondence and requests for reprints to: Dr. D. R. Armant, Department of Obstetrics and Gynecology, C. S. Mott Center for Human Growth and Development, Wayne State University School of Medicine, 275 East Hancock Avenue, Detroit, Michigan 48201-1415. E-mail: d.armant{at}wayne.edu
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Introduction |
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Steroidal control of HB-EGF expression has been demonstrated in the rodent during uterine receptivity for implantation. HB-EGF complementary DNA (cDNA) was identified in a subtracted cDNA library corresponding to transcripts induced by progesterone in rat uterine stromal cells (3). Ribonuclease (RNase) protection assays and in situ hybridization demonstrated that progesterone induces HB-EGF expression in stroma, but inhibits it in epithelial cells, whereas estrogen treatment has the opposite effect within each cell type. In ovariectomized mice, estrogen induces HB-EGF messenger ribonucleic acid (mRNA) and protein expression specifically in uterine epithelial cells, whereas combined stimulation with estrogen and progesterone induces HB-EGF expression in the stroma (6). Before implantation, HB-EGF is expressed in mouse uterine luminal epithelial cells solely at sites of blastocyst apposition; however, in pregnant ovariectomized mice maintained on progesterone during delayed implantation, HB-EGF expression does not occur at these sites until implantation is initiated by estrogen (2).
Activation of EGF receptor influences blastocyst implantation as well as the subsequent behavior of trophoblast cells during placentation. HB-EGF gene transfection experiments suggest that membrane-bound HB-EGF functions as one of the mediators of blastocyst attachment to the luminal epithelium through its ability to bind heparan sulfate proteoglycans and/or EGF receptors present on the blastocyst (10). Mouse blastocysts treated with HB-EGF during in vitro culture hatch from the zona pellucida more rapidly and produce trophoblast cells with enhanced motility after outgrowth commences (2). In humans, blastocyst formation in vitro and hatching from the zona pellucida are remarkably improved in culture medium supplemented with HB-EGF (15). During placentation, EGF family growth factors may continue to play a critical regulatory role, suggested by data indicating that the invasive capacity of cultured human cytotrophoblast cells is increased by treatment with EGF, but not with several other growth factors (16).
Recent evidence indicates that HB-EGF is expressed in the human uterus during the earliest stages of pregnancy. HB-EGF expression is maximal during the late secretory phase (cycle days 20–24), when the human endometrium becomes receptive for blastocyst implantation (4). During the first trimester of pregnancy, HB-EGF is detected in the chorionic villi (4), demonstrating that trophoblast tissues are capable of expressing HB-EGF. Should expression extend to the extravillous trophoblast, HB-EGF could potentially promote invasiveness through autocrine signaling. To further explore these possibilities, in situ hybridization and immunohistochemistry were performed to determine the cell-specific localization of HB-EGF mRNA and protein in human uterine tissues. The results reveal a broader pattern of HB-EGF expression in the human endometrium than previously reported, which includes secretory stage stromal cells and blood vessel endothelium as well as accumulation in the decidua and extravillous trophoblast cells during early pregnancy.
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Materials and Methods |
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Signed informed consent approved by the Wayne State University
human investigations committee was obtained from all human subjects.
The study subjects were between the ages of 18–35 yr and had not
undergone hormonal treatment during the previous 3 months.
Hysterectomies were performed for indications of uterine leiomyomas or
cervical pathology. Uterine specimens from nonpregnant patients (n
= 26) were collected at the time of hysterectomy, immediately
transported to the pathology department on ice, and cleared for further
study by a pathologist. Endometrial tissue (
1 x 1 cm) from the
fundal region not overlying leiomyomas was either immersed in cold OCT
compound (Tissue Tek, Elkhart, IN), snap-frozen in liquid nitrogen, and
stored at -70 C or fixed for 6 h in 3.7% buffered formaldehyde
and embedded in paraffin. Archived pathology specimens from
terminations performed between weeks 6–8 of pregnancy (n = 4)
were used for analysis of trophoblast and decidua. Tissues from
implantation sites had been fixed in formaldehyde and embedded in
paraffin.
Immunohistochemical analysis
Cryostat sections (4 µm) cut from frozen endometrial tissues were mounted on poly-L-lysine-treated slides, fixed in acetone at 4 C for 10 min, dried at room temperature for 30 min, and rehydrated in phosphate-buffered saline (PBS) for 10 min. Paraffin-embedded sections were cut at 4 µm, deparaffinized, and heated three times for 3 min each time in a microwave oven set at 80% power. For histological staging of the endometrium (performed by N.D.R.) (17), some slides were stained with hematoxylin and eosin. Sections stained for HB-EGF were incubated with 5% rabbit serum for 20 min, whereas sections stained for progesterone receptor were incubated with 5% horse serum. Polyclonal goat antibody (IgG) raised against recombinant HB-EGF (R&D Systems, Minneapolis, MN) was used at a final concentration of 10 µg/mL. Monoclonal antibodies raised against human progesterone receptor (mouse IgG, MA1–410, Affinity BioReagents, Inc., Golden, CO) or cytokeratin (rat IgG, 7D3, a gift from Drs. Yan Zhou and Caroline Damsky, University of California, San Francisco, CA) (18) were diluted to 5 µg/mL or 1:200, respectively. The specificity of the MA1–410 antibody was characterized by the absence of bands on Western blots after neutralization with synthetic peptide antigen (data not shown). All antibodies were applied to the mounted tissue sections for 45 min at 25 C. Negative control sections were incubated with nonimmune goat, rat, or mouse IgG (Sigma Chemical Co., St. Louis, MO) or neutralized by adding 100 µg/mL recombinant HB-EGF (R&D Systems) to the antibody. The slides were then incubated for 10 min at 25 C with 1:100 biotinylated rabbit antigoat, horse antimouse, or goat antirat IgG (Jackson ImmunoResearch Laboratories, Inc., West Grove, PA), as appropriate. After rinsing with PBS, the bound antibodies were visualized using avidin-biotin complex with peroxidase (ABC; Vector Laboratories, Inc. Burlingame, CA). All slides were counterstained with hematoxylin. The staining intensity in each tissue region was semiquantified (19) using a subjective score (from 0–3) that was provided by two blinded examiners.
Hybridization probe
A 658-bp (nucleotides 303–960, accession no. M60278) fragment of the cDNA clone for human HB-EGF (7) was inserted into a PstI site of the pGEM-7Zf(+) vector (Promega Corp., Madison, WI) and used as a template for the SP6-directed (antisense) or T7-directed (sense) 35S-labeled complementary RNA probes. Probes had specific activities of about 2 x 109 dpm/µg.
In situ hybridization
In situ hybridization of HB-EGF mRNA was performed as previously described (20), using specimens from nonpregnant patients on cycle days 15, 18, and 22. Frozen sections of tissue (10 µm) from each specimen were mounted together on poly-L-lysine-coated slides, fixed in 4% paraformaldehyde, and acylated. Samples were incubated for 10 min in PBS containing 5 mmol/L MgCl2, 0.25 mol/L Tris, and 0.1 mol/L glycine, pH 7.0, then at 37 C in 50% formamide prepared in 2X SET (1 x SET = 150 mmol/L NaCl, 5 mmol/L ethylenediamine tetraacetate, and 10 mmol/L Tris-HCl, pH 8.0). Hybridization was carried out in a humidified chamber for 5 h at 42 C in 100 µl containing 2 x SET; 10 x Denhardt’s solution; 50% formamide; 100 mmol/L dithiothreitol; 250 µg/mL yeast transfer RNA; 10% dextran sulfate; 0.2% each of BSA, Ficoll, and polyvinylpyrrolidone; and 2.0 x 106 cpm/mL sense (control) or antisense [35S]complementary RNA probe. After hybridization, the siliconized coverslips were removed by washing in 4 x SSC. Slides were incubated at 37 C for 30 min with 20 µg/mL RNase A and 100 µg/mL BSA in 3 x SET. After a 30-min wash in 0.2 x SSC and 0.1% mercaptoethanol, the hybridized probe was detected by autoradiography using Kodak NTB-2 liquid emulsion (Eastman Kodak Co., Rochester, NY) and an exposure time of 5–10 days. The slides were lightly counterstained with hematoxylin and eosin.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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)
revealed several pertinent developmental patterns. Endometrial glands
and endothelial cells within uterine blood vessels expressed maximal
levels of HB-EGF on cycle days 20–24, coinciding with the period of
uterine receptivity for blastocyst implantation. From cycle days
10–18, HB-EGF expression gradually increased to peak levels with
increasing progesterone levels, followed by a rapid decline to
preovulatory levels by cycle day 26. In contrast, stromal cell
accumulation of HB-EGF rapidly increased during the preovulatory period
to a maximal level on cycle day 13 and declined thereafter. After cycle
day 18, stromal cells continued to accumulate modest levels of HB-EGF
in a few specimens until day 28.
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), but decreased to lower
levels by cycle day 22 (Fig. 2B). In the luminal and glandular
epithelia on cycle days 22 and 24, HB-EGF was abundant in the cytoplasm
and also appeared on apical cell surfaces (Fig. 2, B and C). In
addition, HB-EGF was expressed in the endothelium of blood vessels
throughout the uterus during this period (Fig. 2D). Myometrium stained
moderately without apparent changes throughout the menstrual cycle
(data not shown). No staining was observed when recombinant HB-EGF was
used to neutralize the primary antibody (Fig. 2E) or when nonimmune
goat IgG was added in place of the primary antibody (Fig. 2F).
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). Regions of both high (Fig. 3, arrows) and low signal intensity were observed throughout
the endometrium. Only background levels of hybridization were obtained
with the sense control probe (data not shown).
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), as previously reported (21).
Human implantation sites were examined to assess cell-specific HB-EGF
expression during pregnancy. Both cytotrophoblast and
syncytiotrophoblast of the chorionic villi showed accumulation of
HB-EGF, although the former stained more strongly in most specimens
(Fig. 4, A and B). Endothelial cells of
blood vessels within the chorionic villi were also positively stained
(Fig. 4B). The expression of cytokeratin was used to identify
extravillous trophoblast cells infiltrating the placental bed.
Cytokeratin-positive cells were abundant throughout the decidua and
within uterine blood vessels of the basal plate regions (Fig. 4C).
Staining of HB-EGF throughout the basal plate indicated that HB-EGF
accumulated in both extravillous trophoblast cells and neighboring
decidual cells, although the heaviest labeling appeared to be
associated with cytotrophoblast cells near blood vessels and the
cytotrophoblastic shell (Fig. 4D). Nonimmune rat or goat IgG did not
stain the tissue when substituted for the anticytokeratin or
anti-HB-EGF antibodies (Fig. 4, C' and D').
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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HB-EGF mRNA is detected throughout the endometrial cycle, as determined using RT-PCR (22). The latter observation is consistent with the broad expression of HB-EGF protein that we report here. Using in situ hybridization, HB-EGF mRNA expression was detected specifically in the stroma on cycle day 18 and switched to the glandular epithelium by cycle day 22, suggesting that the observed changes in the cell-specific accumulation of HB-EGF protein reflected de novo synthesis. The abundant labeling of HB-EGF mRNA observed in the subepithelial stroma on cycle day 18 coincides temporally with the highest transcript levels detected in endometrial samples by RNase protection assay (4). Both HB-EGF mRNA and protein accumulated in a nonuniform distribution in the endometrium. Nonuniform expression patterns are not uncommon within the endometrium (23). Because HB-EGF is a secreted product, the protein may not remain localized at its site of synthesis, which may explain why on cycle day 18 HB-EGF mRNA was localized in the subepithelial stromal, whereas its protein accumulated in the epithelium. The broad immunostaining pattern for HB-EGF within the placental bed may similarly reflect accumulation in the decidua of protein synthesized by the extravillous cytotrophoblast, which were most heavily labeled by the antibody.
Epithelial expression of HB-EGF protein was maximal with the initiation
of the decline in progesterone receptors. Consistent with previous
observations (21), progesterone receptor levels increased in the glands
during the proliferative phase, followed by a sharp decline beginning
on cycle day 18. The pattern of progesterone receptor expression in the
glands provided corroborating evidence that the histological dating of
uterine specimens was correct. Down-regulation of progesterone
receptors on cycle day 20 is closely linked to the elevated expression
of 
Vß3 and placental protein 14, both
markers of uterine receptivity (24, 25, 26). In an endometrial
adenocarcinoma cell line that responds to steroids in a manner similar
to uterine epithelial cells in vivo, addition of either EGF
or transforming growth factor- significantly increases the
expression of Vß3, whereas treatment with
progesterone and estrogen down-regulates this integrin (27). Integrin
expression is induced by HB-EGF in some cancer cells (28, 29). HB-EGF
expression in the endometrium remains elevated during a period when the
number of epithelial receptors for estrogen and progesterone decline
(21). Therefore, in the absence of epithelial responsiveness to
steroids, the functional maturation of the secretory endometrium to its
receptive state may depend on growth factors such as HB-EGF that can
increase the expression of integrins or other proteins that mediate
blastocyst implantation.
In the nonpregnant uterus, endothelial expression of HB-EGF was
correlated with the endometrial cycle, peaking during the receptive
phase. Previously, endothelial cells were found to express HB-EGF when
treated with tumor necrosis factor- (30). HB-EGF expression by
uterine endothelial cells may be mitogenic for endothelial cells or
smooth muscle cells and contribute to uterine vascular remodeling
during early pregnancy. This would be consistent with the observed
proliferation of vascular smooth muscle cells under autocrine or
paracrine stimulation by HB-EGF (31, 32). Vascular remodeling also
occurs in the chorionic villi, where additional endothelial HB-EGF
expression was observed. The ability of HB-EGF to modulate integrin
expression (28, 29) and cell motility (2, 11) and its role as a
chemoattractant (14, 33) suggest an underlying role in cytotrophoblast
invasion of the vasculature (34). Moreover, HB-EGF may transform
cytotrophoblast cells to a noninvasive, vascular phenotype, which is
known to occur during invasion of the spiral arteries (35).
We examined HB-EGF protein accumulation within the placental bed, demonstrating that cytokeratin-positive extravillous cytotrophoblast cells accumulate high levels of the growth factor. This finding is consistent with previous observations that HB-EGF mRNA and protein accumulate in first trimester villous cytotrophoblast (4, 22) and that mRNA is present in decidua (22). Before week 10 of pregnancy, the implantation site constitutes a hypoxic environment (36). We speculate that the observed accumulation of HB-EGF throughout implantation sites during weeks 6–8 of gestation may reflect the induction of HB-EGF by hypoxia. Hypoxic induction of HB-EGF has been observed in a kidney ischemia-reperfusion model (37) and in rat gastric epithelial cells exposed to peroxide (38). Administration of HB-EGF to animals or cultured cells during exposure to hypoxic conditions diminishes the severity of organ damage and significantly lowers cell death rates (39, 40). The mechanism of protection by HB-EGF is not completely understood, but appears to be related the preservation of cytoskeletal integrity (40). The ability of trophoblast cells to proliferate under hypoxic conditions (41, 42), whereas other cell types are damaged, may result in part from the cytoprotective effect of HB-EGF within the implantation site.
The expression of HB-EGF in several distinct cell populations throughout the implantation site suggests that physiological responses to HB-EGF may differ widely with cell type. For example, HB-EGF may promote the proliferation of trophoblast cells within the chorionic villi while it maintains invasiveness of the extravillous cytotrophoblast cells. The complement of EGF receptor subtypes expressed by a cell determines the physiological effects of EGF family ligands (14). HER1 and HER2 are expressed differentially by trophoblast populations; HER1 predominates in the villous cytotrophoblast, whereas HER2 is found in the syncytiotrophoblast and cytotrophoblast cells in the distal portion of the anchoring villi (43). The cell-specific expression of other EGF receptor subtypes within implantation sites has not yet been reported. It is, therefore, anticipated that the differential expression of EGF receptor subtypes by phenotypically diverse trophoblast populations mediates varied biological responses to HB-EGF encountered locally during implantation and placentation.
Our studies have revealed intriguing cell-specific patterns of HB-EGF expression in the human uterus during the endometrial cycle and within implantation sites from weeks 6–8 of pregnancy. HB-EGF expression appears to be under ovarian steroidal control during the endometrial cycle. During pregnancy, HB-EGF accumulates in both uterine and trophoblast cell populations, suggesting that it functions in a variety of cellular processes that may include mitogenesis, the promotion of trophoblast invasion, cytoprotection from hypoxia, and vascular remodeling. These varied responses may result from local expression of the transmembrane or secreted forms of HB-EGF or from the expression patterns for EGF receptor subtypes in the target cells.
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Acknowledgments |
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Footnotes |
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Received October 9, 1998.
Revised February 3, 1999.
Revised April 28, 1999.
Accepted June 3, 1999.
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