Molecular Human Reproduction, Vol. 6, No. 10, 959-965,
October 2000
© 2000 European Society of Human Reproduction and Embryology
Pregnancy |
Local fetal signal is not required for maintaining IGFBP gene expression in the human decidua: evidence from extrauterine pregnancies
1 MRC Group in Fetal and Neonatal Health and Development, The Lawson Research Institute, The Child Health Research Institute, and Departments of Pediatrics, Obstetrics and Gynaecology, and Biochemistry, University of Western Ontario, London, Canada, 2 Department of Pathology, University of Western Ontario, London, Canada and 3 Department of Obstetrics and Gynaecology, University of Giessen, Giessen, Germany
Abstract
Insulin-like growth factor-II (IGF-II) from the invading extravillous cytotrophoblasts (EVTs) and insulin-like growth factor binding proteins (IGFBPs) from the maternal decidua interact at the feto–maternal interface and regulate implantation and placentation. To determine whether a local stimulus from the fetus is important in the regulation of IGFBP gene expression in the human decidua, we compared the expression of IGFBP genes in intra- and extrauterine (tubal) pregnancies. The expression of IGF-II and IGFBP-1 to IGFBP-6 mRNAs was determined by in-situ hybridization in the Fallopian tubes of extrauterine pregnancies and concurrent decidua (n = 6), and in the placentae and Fallopian tubes of intrauterine pregnancies (n = 6). All six IGFBP mRNAs were identified in the decidualized endometrium and decidualized Fallopian tubes of intra- and extrauterine pregnancies, with IGFBP-1 mRNA being the predominant mRNA. IGFBP-4 was the second most predominant mRNA and was slightly more abundant in the decidua of extrauterine pregnancies than of intrauterine pregnancies. IGF-II mRNA was expressed mainly in cells of fetal origin. The fact that the IGFBP mRNAs were expressed similarly in both intra- and extrauterine pregnancies indicates that the local physical stimulus from an implanting fetus is not necessary to induce or maintain decidual IGFBP gene expression.
decidual cells/endometrium/extrauterine pregnancy/IGF-II
Introduction
The development of a haemochorial placenta involves invasion of extravillous trophoblasts (EVTs) into the uterine wall and remodelling of the utero–placental vessels (Enders, 1968
; Bernischke and Kaufman, 1990). In contrast to tumour growth and invasion, trophoblastic invasion during the early stages of placentation is a well co-ordinated and regulated process (Graham and Lala, 1991; Fischer and Damsky, 1993). A large number of factors play different roles in the regulation of trophoblast migration, proliferation and invasion. Because of a poorly developed circulation in the early stages of placentation, short-range regulatory loops have been proposed to modulate trophoblastic invasion (Ohlsson et al., 1989a; Bischof et al., 1998). Insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) are believed to participate in one of these loops. IGFs and IGFBPs also mediate and modulate steroid hormone actions in the endometrium during the menstrual cycle and implantation (Bell, 1989; Zhou and Bondy, 1992; Rutanen, 1998). Recent studies have shown that IGF-II, expressed in the invading trophoblast, and IGFBP-1, the major binding protein expressed in the maternal decidua, participate in cell–cell interaction which regulates the invasion of EVTs (Han et al., 1996; Hamilton et al., 1998). IGFBPs modulate the IGF–IGF receptor interaction during this process in a paracrine manner (Jones and Clemmons, 1995). In addition, some IGFBPs may have IGF-independent actions, that may be mediated via their own specific receptors (Oh, 1997). Before implantation, maternal endocrine factors (e.g. progesterone, chorionic gonadotrophin) regulate IGFBP gene expression in the uterus (Irwin et al., 1994; Tang et al., 1994; Fazleabas et al., 1997; Guidice and Irwin, 1999). Once implantation has occurred, paracrine growth factors and cytokines secreted by trophectoderm and early placenta, and systemic hormones secreted by the ovary may influence IGFBP gene expression in the endometrium (Han et al., 1999).
Previous studies in experimental animals with pseudopregnancy, in which endometrial and myometrial IGFBP gene expression is induced by hormonal priming followed by local stimulation, suggest that endometrial IGFBP gene expression may not require a local fetal or placental stimulus in rodents (Heynemyre and Markoff, 1998). Our previous studies have shown that there are significant differences in the spatial and temporal patterns of expression of IGFBP genes between humans and rodents (Han and Carter, 2000). In rodents, IGFBP genes are expressed predominantly in the myometrium, whereas in humans they are expressed in the decidua. Therefore, to determine whether IGFBP gene expression in human decidua requires a local fetal or placental stimulus, we used the paradigm presented by the pathological condition of tubal pregnancy, in which the endometrium is stimulated by maternal and fetal (placental) hormones to decidualize without direct contact with the conceptus. In addition, we compared the expression of IGF and IGFBP genes in tubal decidualization (a common histological change occurring in normal pregnancy and which was seen in all our specimens), with that of normal intrauterine decidualization.
Materials and methods
Tissues
Representative samples of extrauterine tubal pregnancies were obtained by laparoscopic salpingectomy and the concurrent endometrium were obtained by curettage (n = 6). Placentae with concurrent fragments of Fallopian tube were obtained from legal abortions with tubal ligation procedure at 6–8 weeks gestation (n = 6). Samples were fixed in 10% neutral-buffered formalin and processed for paraffin embedding by standard methods. Sections (5 µm) were prepared and mounted on Superfrost Plus slides (Fisher Scientific, Fairlawn, NJ, USA). The tissue collections were made in accordance with the hospital consent for the pathological investigation, and the ethics committees of the University of Western Ontario (London, Canada) and the University of Giessen (Giessen, Germany) approved the protocols.
In-situ hybridization
In-situ hybridization was performed as described previously (Han et al., 1996). Briefly, 5 µm tissue sections were deparaffinized, rehydrated and after prehybridization, hybridized with [35S]-labelled antisense complementary RNA (cRNA) or sense RNA probes overnight at 55°C, and washed at maximum stringency with 0.1x standard sodium chloride/sodium citrate (SSC) at 65°C for 30 min. The [35S]-radiolabelled antisense and sense RNA probes were generated from the following complementary DNAs (cDNAs): human IGF-II cDNA (a gift from Dr M.Jansen, University of Utrecht, The Netherlands) subcloned into pGEM-4Z vector (Promega, Madison, WI, USA), human IGFBP-1 to IGFBP-6 cDNAs subcloned in pBluescript-SK vectors (gifts from S.Shimasaki, University of California, San Diego, CA, USA). Sections were dehydrated, coated with photoemulsion (NTB-3 nuclear track emulsion; Eastman Kodak Laboratories, Rochester, NY, USA), and exposed at 4°C for 2 weeks. The photoemulsion was developed with a D-19 developer (Eastman Kodak Laboratories), fixed, stained with Harris's haematoxylin and eosin, and mounted with Permount (Fisher Scientific). The specificity of in-situ hybridization was demonstrated by the lack of specific hybridization signal when adjacent tissue sections were subjected to an identical in-situ hybridization procedure with radiolabelled sense cRNA probes.
Immunohistochemistry
Double staining of sections of the feto–maternal region, of the Fallopian tube and endometrium was performed for cytokeratin, a marker for trophoblast and epithelial cells, using a polyclonal antiserum against polyvalent cytokeratin (1:1000; Dako, Glostrup, Denmark), and for vimentin, a marker for decidual and mesenchymal cells, using a monoclonal antibody against human vimentin (1:50, Dako). The immunoreactivity was visualized with the avidin– biotin–peroxidase system using diaminobenzidine as the chromagen (Vincastain; Vector Laboratories, Burlingame, CA, USA).
Results
Distribution pattern of IGFBP mRNAs in the decidua of extra- and intrauterine pregnancies
In the decidua of extrauterine tubal pregnancies, all six IGFBP mRNAs were detected. IGFBP-1 and IGFBP-4 were the predominant IGFBPs of the decidualized stromal cells. IGFBP-1 mRNA was expressed both in the epithelium of endometrial glands and in the decidualized stromal cells, although in non-decidualized regions IGFBP-1 mRNA expression was restricted to the glands. Other IGFBP mRNAs were expressed in low abundance (IGFBP-2, IGFBP-3, IGFBP-5) or very low abundance (IGFBP-6). The distribution and relative abundance of mRNAs encoding IGFBP-1 to IGFBP-6 in the decidua of extrauterine pregnancies are shown in Figure 1 (right panel) and summarized in Table I. Isolated cells of mesenchymal origin, as noted by vimentin immunoreactivity within the decidua, also expressed very low amounts of IGF-II mRNA.
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In the decidua of intrauterine pregnancies at 6 weeks gestation, IGFBP-1 mRNA was expressed in groups of epithelial cells in the decidual glands and in some cells of decidual stroma. At 8 weeks gestation, the majority of IGFBP-1 mRNA was expressed in decidual stromal cells. During early gestation, IGFBP-4 mRNA was detected in stromal cells in moderate abundance. Other IGFBP mRNAs (IGFBP-2, IGFBP-3, IGFBP-5 and IGFBP-6) showed a low expression. The distribution and relative abundance of mRNAs encoding IGFBP-1 to IGFBP-6 in the decidua of intrauterine pregnancies are shown in Figure 1
(left panel) and summarized in Table I. Although IGFBP-4 mRNA appeared to be slightly more abundant in the decidua of extrauterine pregnancies, there were no significant differences in the expression of IGFBP mRNAs between intra- and extrauterine pregnancies.
Distribution pattern of IGF-II mRNA in extrauterine pregnancies
IGF-II mRNA was expressed predominantly in cells of fetal origin (cytotrophoblast and chorionic mesoderm) and was identified in the cytotrophoblast of the anchoring villi and in the EVTs invading the Fallopian tube. However, IGF-II mRNA was not expressed in the syncytiotrophoblast (Figure 2A and B). In the maternal tissue, IGF-II mRNA was expressed in low abundance in the decidual stroma.
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Distribution pattern of IGFBP mRNAs in the Fallopian tube of extrauterine pregnancies
IGFBP-1 and IGFBP-4 mRNAs were abundantly expressed in the tubal wall of extrauterine pregnancies (Figure 2C and D
). IGFBP-1 mRNA was expressed in relatively greater abundance than IGFBP-4 mRNA. Other IGFBP mRNAs were expressed in moderate (IGFBP-3) to low (IGFBP-2, IGFBP-5) or very low abundance (IGFBP-6) showing a similar pattern of IGFBPs mRNA expression as the concurrent decidua. IGFBP-3 mRNA was the only IGFBP mRNA expressed in the fetal tissue (extravillous trophoblast). The highest IGFBP-3 mRNA expression was seen in the cytotrophoblast invading maternal tissue. The expression patterns of IGFBP-3 mRNA were similar between intra- and extrauterine implantations.
Distribution pattern of IGFBPs mRNA in the Fallopian tube of normal pregnancies
Since the Fallopian tube undergoes endocrine-related changes similar to those of uterine endometrium during pregnancy, we examined Fallopian tube sections from elective tubal ligation procedures. According to their morphological appearance, strongly decidualized and relatively preserved non-decidualized segments of the tubal wall could be detected in these specimens. We showed that abundant IGFBP-1 mRNA was abundant in decidualized, but not in non-decidualized, segments of the tubal wall in intrauterine pregnancies. Other IGFBP mRNAs were expressed in moderate (IGFBP-3 and IGFBP-4) to low or very low abundance (IGFBP-2, IGFBP-5 and IGFBP-6). The distribution and relative abundance of mRNAs encoding IGFBP-1, IGFBP-3 and IGFBP-4 in the Fallopian tube are shown in Figure 3.
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Discussion
The spatial and temporal pattern of IGFBP and IGF-II gene expression at the feto–maternal interface suggests an important physiological role of these molecules in the process of implantation and placentation. IGF-II mRNA is abundantly expressed in the fetal EVTs and IGFBPs are expressed in the maternal decidua (Zhou and Bondy, 1992; Han et al., 1996; Giudice and Irwin, 1999). This well-demarcated spatial pattern of expression also indicates the potential role of IGF-II in the induction of IGFBPs mRNA (Ohlsson et al., 1989b; Liu et al., 1995; Coulter and Han, 1996; Han et al., 1996).
Little information is available on the factors that determine the expression of IGFBPs and IGF-II at the feto–maternal interface, especially with regard to the regulation of IGFBPs after implantation. Previous studies have utilized in-vitro decidualization to study the regulation of expression of IGFBP genes in decidual stromal cells (Tabanelli et al., 1992; Myers et al., 1993; Irwin et al., 1994). However, the process of separation and isolation of decidual stromal cells from their natural context of the uterine environment, creates an artificial situation in which the gene expression pattern of these cells may not reflect the situation in vivo. In this study, we used both the decidualized endometrium and tubal specimens of intra- and extrauterine (tubal) pregnancies (as conditions in which trophoblast and decidua are in their natural context), to determine whether the local presence of an embryo or trophoblast, are required to maintain or induce IGFBP expression in the decidua.
Due to the spatial separation of the site of implantation, which occurs in the Fallopian tube, from decidualized endometrium, extrauterine pregnancy is an appropriate model for the examination of the induction and maintenance of the expression of IGF and IGFBP genes in the early stages of pregnancy. Extrauterine pregnancies occur in most cases as a tubal pregnancy with intraluminal trophoblast spreading, and in ~40% of cases, a deep invasion of the Fallopian tube by the trophoblastic cells occurs (Pfeiderer et al., 1999). Tubal epithelium undergoes similar changes as the uterine endometrium during the preimplantation phase and the tubal stroma cells transform into decidual cells (Pfeifer and Chegini, 1994). If the conceptus is important in the regulation of IGFBP gene expression, it is expected that the expression of IGFBP genes in the decidua of the extrauterine pregnancy will be different from that of a normal intrauterine implantation.
We showed in this study that in human pregnancy local signals from the fetus or placenta are not required for maintaining decidual IGFBPs gene expression since the decidual IGFBP mRNAs expression patterns do not differ between extra- and intrauterine implantation. Our observations of the tubal decidua of normal and extrauterine pregnancies in which most of the IGFBP mRNAs, except IGFBP-6 mRNA, are expressed in a similar pattern and relative abundance present an additional evidence that IGFBP gene expression is concomitant to decidualization and is independent of local signals from the conceptus. IGFBP-1 mRNA was abundantly expressed in the decidualized endometrium and tubal wall of extrauterine pregnancies. In normal pregnancy, where the Fallopian tube was occasionally decidualized, IGFBP-1 mRNA was also highly abundant. IGFBP-1 mRNA in the Fallopian tube was heterogeneous and restricted to some decidualized stroma cells. In non-decidualized stromal cells, IGFBP-1 mRNA was not expressed, even when trophoblast cells were seen invading into this area. These findings suggest that the expression of IGFBP-1 mRNA is pari passu to the hormonally-induced differentiation of endometrial or tubal stromal cells into decidua, rather than to that induced locally by the conceptus. These findings are in agreement with a previously described high level of expression of IGFBP-1 protein in extrauterine decidualized stromal cells (Rutanen et al., 1991). Previously it has been shown that oestradiol in the rat (Molnar and Murphy, 1994) and progesterone alone or combined with 17ß-oestradiol in human endometrial stromal cells induce decidualization. The latter effect is shown to be linked to the expression of a novel cadherin-11 by the decidua (Chen et al., 1999). The regulation of IGFBP-1 gene expression by glucocorticoids and cyclic AMP is mediated by the transcription factor, HNF1, (Lee et al., 1997), which is itself regulated by insulin by a forkhead/winged-helix transcription factor, FKHR, (Guo et al., 1999). It is possible that both transcription factors play regulatory roles in the expression of IGFBP-1 gene in the decidua.
Similar to intrauterine pregnancies, all other IGFBP mRNAs (IGFBP-2, IGFBP-4, IGFBP-5, and IGFBP-6) were detected in the decidualized endometrium and the Fallopian tube of extrauterine pregnancies (Han et al., 1996). Although IGFBP-1 mRNA is the most abundant, IGFBP-4 mRNA was expressed slightly more abundantly in the decidua of extrauterine pregnancies, compared with normal pregnancies. IGFBP-4 has been described as the major IGFBP mRNA in the mouse uterus, a species having similar placentation to that in man (Markoff et al., 1995). IGFBP-4 mRNA is dramatically increased in the uterine stroma underlying the luminal epithelium at the time of implantation. Subsequently, it is abundantly expressed in the decidua. In the human, IGFBP-4 mRNA is preferentially expressed in the secretory endometrium (Han and Carter, 2000) and, during pregnancy, is expressed in low to moderate abundance in the decidua (Han et al., 1996). The reason for the increased expression of IGFBP-4 mRNA in the decidua of extrauterine pregnancy is unknown; however, it may be due to differences in the implantation pattern or different proliferative activity of the ectopic trophoblast (Klein et al., 1995) with subsequent plateauing or decreasing concentrations of human chorionic gonadotrophin (HCG). Since high HCG concentrations suppress IGFBP-4 gene expression in distinct cell systems, decreasing HCG concentrations may up-regulate IGFBP-4 gene expression (Huynh, 1998). Decreasing HCG may also up-regulate progesterone synthesis in the corpus luteum with subsequent progesterone-induced IGFBP-4 expression in stromal cells (Hagstrom et al., 1996). Recent studies have also shown that IGF-II up-regulates IGFBP-4 proteases during pregnancy, suggesting a possible loop in the regulation of IGFBP-4 expression (Byun et al., 2000).
The expression of IGF-II gene was restricted to the trophoblast invading maternal tissue (Fallopian tube) in extrauterine implantation. The pattern of expression is similar to that observed in the implantation site of normal first trimester pregnancies (Han et al., 1996). This finding supports our hypothesis that IGF-II plays an important role in the migration and invasion of the cells, irrespective of the site of embryo implantation (Hamilton et al., 1998). Other investigators have shown that the high level of IGF-II mRNA expression in the trophoblast is a post-implantation event and that endogenously produced IGF-II participates in the formation of the invasive phenotype of the trophoblastic shell following implantation (Coulter and Han, 1996).
Our findings in this study suggest that the induction and maintenance of the IGFBP gene expression by decidualized stromal cells occur in a similar manner, irrespective of the site of implantation. It is clear from our current study that local signals from the invading trophoblasts are not required for maintaining decidual IGFBP gene expression, except perhaps for the slight derepression of IGFBP-4 gene expression. The hormonal signals arising from the implanting conceptus or the ovary are adequate for the induction of the IGFBP genes. Thus, in humans, the uterine endometrial stroma differentiates into decidua under hormonal control in preparation for the receipt of the implanting conceptus, which over-expresses IGF-II. This preparation is essential for a successful implantation and pregnancy.
Acknowledgments
The work was supported by a Visiting Scientist Grant from the German Research Council (DFG) (to M.Z.) and the Group grant in Fetal and Neonatal Health and Development from the Medical Research Council of Canada (MRC) (to V.K.M.H.).
Notes
4 To whom correspondence should be addressed at: H308, The Lawson Research Institute, 268 Grosvenor Street, London, Ontario, Canada. E-mail: vhan{at}julian.uwo.ca 
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