Placenta
Volume 29, Supplement 2 , Pages 129-134, October 2008

Inflammatory Reaction and Implantation: the New Entries PTX3 and D6

  • C. Garlanda

      Affiliations

    • Istituto Clinico Humanitas IRCCS, via Manzoni 56, I-20089, Rozzano, Milan, Italy
    • Corresponding Author InformationCorresponding author. Tel.: +39 02 82245115; fax: +39 02 82245101.
    • ,
  • V. Maina

      Affiliations

    • Istituto Clinico Humanitas IRCCS, via Manzoni 56, I-20089, Rozzano, Milan, Italy
    • ,
  • Y. Martinez de la Torre

      Affiliations

    • Istituto Clinico Humanitas IRCCS, via Manzoni 56, I-20089, Rozzano, Milan, Italy
    • ,
  • M. Nebuloni

      Affiliations

    • Pathology Unit, Luigi Sacco Department of Clinical Sciences, University of Milan, Milan, Italy
    • ,
  • M. Locati

      Affiliations

    • Istituto Clinico Humanitas IRCCS, via Manzoni 56, I-20089, Rozzano, Milan, Italy
    • Institute of General Pathology, University of Milan, Milan, Italy

Accepted 20 June 2008. published online 04 August 2008.

Article Outline

Abstract 

Successful embryonic implantation implies anchoring the conceptus in the maternal uterine wall, establishing a vascular supply to enable optimal growth and development of the conceptus, and promoting tolerance of fetal alloantigens encoded by paternal genes. To achieve these goals, complex molecular dialogues take place among the maternal endometrium, the conceptus, and the placenta. Several factors are involved in the fetal–maternal interaction, including hormones, growth factors, cytokines, chemokines, adhesion molecules, extracellular matrix components, and matrix-degrading enzymes. This complex cross-talk results in the induction of a local inflammatory response and a state of systemic inflammation, as revealed by leukocytosis, endothelium activation, increased activity of innate immune cells, and increased levels of inflammatory cytokines and chemokines. The enriched cytokine milieu associated to implantation is likely to control trophoblast migration and differentiation, leukocyte influx and activation, complement activation, as well as angiogenic and angiostatic processes in the implantation site. Finally, these mediators play a key role in tuning the immune responses to protect the fetus from infections as well as from maternal rejection. Here, the role of pro-inflammatory networks activated in implantation will be discussed. In particular, emphasis will be put on two new players involved in regulating inflammation at the maternal–fetal interface: the long pentraxin PTX3 and the decoy receptor for inflammatory chemokines D6.

Keywords: Implantation, Inflammation, Chemokine, Pentraxin

 

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1. Implantation and inflammatory networks 

In most mammals there is a very restricted period of time during each reproductive cycle in which the endometrium is receptive to blastocyst implantation. During this so-called ‘implantation window’, changes in the endometrial epithelium and remodelling and differentiation of the stroma occur. The process of endometrium transformation, which occurs only in the presence of progesterone following estrogen priming, is called decidualization, and involves the differentiation of endometrial stromal cells in decidual cells, infiltration by large number of leukocytes, modification of the extracellular matrix (ECM), and increase in vascular permeability [1]. In women, it occurs to a variable extent during the late secretory phase of the cycle in periarteriolar and subepithelial cells, and progresses throughout the stromal compartment with establishment of pregnancy.

The process of implantation begins when the embryonic trophectoderm of a competent blastocyst establishes contact with the luminal epithelium of the uterus. This interaction involves molecules also used during leukocyte extravasation, including trophoblast l-selectin and oligosaccharide-based selectin ligands expressed by the uterine epithelium during the implantation window, and integrins, αvβ3 in particular, expressed by both the endometrium and the cytotrophoblast [2], [3]. Then, the invasive phase of implantation follows: this lasts until approximately 20 weeks of gestation, and is directed by differentiated trophoblasts and various cell types in the decidua [3]. This invasive phenotype is regulated by the controlled production of MMPs that degrade the decidual ECM by trophoblasts and their inhibitors (TIMPs) by the decidual stromal cells. During this phase, interstitial cytotrophoblasts invade the underlying decidua, surround and penetrate spiral arteries and arterioles, and become endovascular cytotrophoblasts that transform the smooth muscle layer and endothelium of these vessels [4]. This process converts small-bore, high-resistance vessels to large-bore, low-resistance vessels that meet the demands of the growing feto–placental unit by increasing maternal blood flow. Normal placental development requires coordinated expression of angiogenic growth factors, including Vascular Endothelial Growth Factor (VEGF) and Placenta Growth Factor, as well as expression of their respective receptors on invasive trophoblasts [4]. Impaired endovascular trophoblast invasion is the primary placental defect causing inadequate conversion of the uterine arteries and reduced uteroplacental blood flow and leading to fetal intrauterine growth restriction (IUGR) and the development of preeclampsia, a leading cause of maternal and fetal morbidity and mortality throughout the world [5].

Several studies, including expression profiling studies of decidual cells exposed to trophoblast conditioned medium, demonstrated that decidualized stromal cells have a significant immunomodulatory role and produce several inflammatory mediators [6], [7], [8]. IL-1β and TNFα in particular have emerged as candidate genes responsible for the activation of the pro-inflammatory cascade at the feto–maternal interface [8]. These primary pro-inflammatory cytokines activate a signalling pathway culminating in NF-kB nuclear translocation and subsequent production of secondary mediators as chemokines, COX-2, prostaglandins, MMPs, pentraxin 3 (PTX3) (see below), and to the expression of adhesion molecules [9], [10], [11]. Several components of the IL-1 system (IL-1β, IL-1 Receptor Antagonist, IL-1 Receptor type 1, IL-18) have been detected at the feto–maternal interface. Stromal cells, endometrial epithelial cells as well as trophoblasts are IL-1R1 expressing cells [12] and respond to IL-1β, which is released by human extravillous trophoblasts, macrophages and decidual stromal fibroblasts [13]. IL-1 has been reported to stimulate endometrial production of prostaglandins, LIF, chemokines and MMPs and to induce integrin expression [14], [15], [16]. A prominent role in implantation is also played by the IL-6 family members (IL-11, LIF, and IL-6 itself) [17], which act through a receptor complex composed by a specific receptor α chain and the shared signalling component gp130. IL-11, LIF, IL-6 and their receptors are expressed at the implantation site by several type of cells [1], [12], [17]. IL-11 and LIF play non-redundant roles in implantation [1], [12], [17] and reduced fertility and implantation efficiency have been described in gene-modified mice for IL-6 [18].

Finally, the local production of complement components by many cell types at the feto–maternal interface and the expression of regulatory proteins Decay-Accelerating Factor, Membrane Cofactor Protein, and CD59 in human and Crry in murine syncytiotrophoblast also suggest a contribution of the complement system in normal placenta function, possibly related to innate immune protection against infections and to apoptotic cell removal [19]. Embryo mortality observed in Crry−/− mice suggests that complement inhibition is an absolute requirement for normal pregnancy [20]. Complement activation has emerged as a critical effector mechanism in several pregnancy associated diseases as IUGR or in recurrent spontaneous abortion, i.e., in the antiphospholipid antibody syndrome. The pathogenetic mechanisms of complement-mediated placental and fetal damage are possibly related to recruitment and activation of inflammatory cells within decidual tissue and release of factors that cause placental dysfunction and compromise angiogenesis and fetal growth [21].

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2. Pentraxins in reproductive immunology: the new entry PTX3 

Other than the complement system, the humoral arm of the innate immune system also includes soluble pattern recognition receptors (PRR), such as collectins, ficolins, and pentraxins [22], [23], [24], which represent functional ancestors of antibodies with a key role as effectors and modulators of innate resistance and inflammation.

Pentraxins are a superfamily of phylogenetically conserved multimeric proteins, characterized by the presence of the pentraxin domain [23]. Based on the primary structure of the subunit, pentraxins are divided in short and long pentraxins. C-reactive protein (CRP) and Serum Amyloid P (SAP) component are short pentraxins mainly produced in the liver in response to inflammatory signals and are acute phase proteins in man and mouse, respectively. The prototypic long pentraxin PTX3 is a multifunctional soluble PRR acting as a non-redundant component of the humoral arm of innate immunity and is involved in tuning inflammation, in matrix deposition and in several aspects of female fertility.

PTX3 is a 45kDa protein that assembles to form high molecular weight multimers linked by inter-chain disulfide bounds [25]. The C-terminal domain of PTX3 shares homology with the short pentraxins, whereas the N-terminal domain does not show any significant homology with other known proteins. PTX3 differs from CRP and SAP also for gene organization, cellular source and ligand–binding properties [23].

A variety of cell types produce PTX3 in vitro upon exposure to primary inflammatory signals, such as IL-1β, TNFα, microbial moieties and agonists for Toll Like Receptors, including myeloid dendritic cells, endothelial cells, monocytes, polymorphonuclear cells, adipocytes, fibroblasts, smooth muscle cells, and cells of epithelial origin [23], [26], [27]. A peculiar tissue is the cumulus oophorus, in which PTX3 mRNA expression is restricted to the pre-ovulatory period and is orchestrated by hormonal ovulatory stimuli (FSH or hCG), by oocyte-derived soluble factors and in particular by Growth Differentiation Factor-9 (GDF-9), a member of the TGFβ family [28], [29].

2.1. Roles of PTX3 in innate resistance, inflammation, and angiogenesis 

The multifunctional properties exerted by PTX3 can be at least in part explained by its capacity to interact with a number of different ligands, a characteristic shared with CRP and SAP. In particular, PTX3 binds to the complement component C1q, interacting with C1q globular head (gC1q) [25] and modulating complement activation.

PTX3 can interact with a number of different pathogens: fungi, virus and bacteria facilitating phagocytosis, complement and immune cell activation. Accordingly, studies with gene-modified mice indicated that PTX3 is non-redundant in selected fungal, bacterial and viral infections [22], [30].

Similarly to CRP and SAP, PTX3 binds to apoptotic cells during late phases of apoptosis and prevents inflammatory uptake of late apoptotic cells and antigen presentation by antigen-presenting cells [31]. PTX3 binds Fibroblast Growth Factor-2 (FGF2) through the N-terminal domain, leading to inhibition of FGF2-dependent endothelial and smooth muscle cell proliferation [32]. Thus, PTX3 could act as a “FGF2 decoy” able to sequester the growth factor in an inactive form, thus modulating angiogenesis in various physiopathological conditions.

2.2. Role of PTX3 in female fertility 

In mice, PTX3 deficiency is associated with a severe defect in female fertility [28], [29], [30]. Infertility of PTX3−/− mice is associated to an abnormal cumulus oophorus in which cumulus cells are uniformly dispersed instead of radiating out from a central oocyte. This abnormal location of granulosa cells is due to defective organization and stability of the ECM [29]. The oocyte develops normally in the absence of PTX3, and can be fertilized in vitro, whereas the fertilization failure observed in vivo is due to the defective cumulus expansion [29]. Under ovulatory stimuli cumulus cells express PTX3, which localizes in the ECM [29], [33]. The major integral component of cumulus matrix is hyaluronan, a large glycosaminoglycan responsible for the viscoelastic properties of this matrix. Among the proteins interacting with hyaluronan and participating in the organization of cumulus matrix there are TNF Stimulated Gene 6 (TSG-6), a multifunctional protein associated with inflammation, and Inter-alpha-Trypsin Inhibitor (IαI). PTX3 interacts through the N-terminal domain with the hyaluronic acid binding domain of TSG-6 [29] and with IαI [34]. Thereby, PTX3 may form multimolecular complexes that can cross-link hyaluronan chains through TSG-6 and IαI, playing a crucial and non-redundant role in the assembly, organization and stabilization of the cumulus matrix [34].

Expression of PTX3 mRNA and protein by human cumulus cells [29], [33], [35] suggests that this molecule might have the same role in murine and human female fertility. Studies on PTX3 mRNA in human cumulus cells indicated that PTX3 might be a possible marker for oocyte quality and success in fertilization [33]. PTX3 protein is abundantly present in the follicular fluid, where its concentrations are sixfold higher than in plasma. However, we could not find a correlation between PTX3 levels in follicular fluid at the time of oocyte retrieval and oocyte quality, possibly because PTX3 shedding from the cumulus matrix to the follicular fluid is not a finely regulated phenomenon [35].

Different gene expression studies indicated that PTX3 is one of the most upregulated genes related to inflammation and angiogenesis induced during implantation. In particular, PTX3 was induced in human decidual stromal cells by the trophoblast, in in vitro systems which mimic the alteration of the local immune environment induced by the trophoblast in the process of embryo implantation [7], [8], and was upregulated in implantation sites compared to interimplatation sites in the mouse [6]. Accordingly, defective decidualization and implantation rates were observed in PTX3−/− mice, suggesting a crucial role of PTX3 for endometrial differentiation and preparation for blastocyst invasion [36]. Results obtained by gene expression studies were recently confirmed by Popovici et al., who demonstrated that PTX3 expression is upregulated in human stromal cells by progesterone and by trophoblast conditioned medium or trophoblast explants. Among the factors produced by trophoblast cells, IL-1 significantly induced PTX3 in stromal cells, whereas hCG had no effect [37]. Immunohistochemical analysis of endometrial biopsies and first and third trimester decidua further confirmed PTX3 induction during human pregnancy. In particular, PTX3 was localized in the perivascular connective tissue and, focally, in endothelial cells and in the interstitium of non-pregnant uterus, and was upregulated in the first trimester decidua (Fig. 1). Interestingly, PTX3 expression was particularly high in the decidua in close proximity to trophoblasts. Extracellular localization of PTX3 was also observed in the stroma of stem and terminal villi and in fetal membranes (Fig. 1).

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  • Fig. 1 

    PTX3 expression in human placenta and decidua. Immunohistochemistry on third trimester human placenta shows PTX3 expression in ghost villi (*) and interstium (**) of basal plate (A), in the stroma of stem villi (B), in terminal villi (C), and in the fetal membranes (D). Extracellular distribution of PTX3 in first trimester decidua; endometrial glands (**) are negative. (F) Consecutive sections of first trimester decidua stained with anti-PTX3 and anti-cytokeratin 7 (inset) antibodies: PTX3 expression in decidual stroma among trophoblasts (cytokeratin 7-positive cells, brown stained in the inset). Haematoxylin counterstaining, DAB (O.M. 10× in panels A and D; 20× in panel B, E and F; 40× in panel C).

Beside PTX3, TSG-6 is also upregulated in decidualized endometrial stromal cells after exposure to trophoblast-secreted products: it is possible that, also in this context the two molecules cooperate, for instance in ECM organization, thus modulating the anchoring of the conceptus in the stromal matrix or the migration of the invasive trophoblast through the stroma. However, the precise role of PTX3 in human endometrium continues to be intriguing. Further studies are need to address which of its roles (ECM assembly, angiogenesis, control of complement activation and inflammation, removal of apoptotic cells) are important during pregnancy, from decidualization to implantation, trophoblast invasion and placentation.

2.3. PTX3 as a marker in human pathology 

The similarity to the classic diagnostic CRP has given impetus to efforts aimed at assessing the usefulness of PTX3 as marker in diverse human pathological conditions. Actually, PTX3 behaves as an acute phase response protein since its blood levels, low in normal conditions, increase rapidly and dramatically during inflammatory and infectious conditions, correlating with the severity of the disease, for instance in sepsis and septic shock, in acute myocardial infarction, in atherosclerosis, in autoimmune disorders [22], [38], [39], [40]. Recent results show that pregnancy itself, a condition associated with systemic inflammatory reaction [41], is associated with slight increase in maternal circulating PTX3 levels compared to the non-pregnant condition. Higher maternal PTX3 levels were observed in pregnancies complicated by preeclampsia [42], [43], which represents the clinical manifestation of an endothelial dysfunction as part of an excessive maternal inflammatory response to pregnancy [44]. This endothelial dysfunction would lead to the activation and dismission in the systemic maternal circulation of inflammatory factors, like cytokines and growth factors (TNFα, IL-1), which are involved in inducing PTX3 expression. Since preeclampsia shares the inflammatory basis with the atherogenic process, we hypothesize a role of this molecule in the endothelial dysfunction typical of preeclampsia. Further studies are necessary to clarify PTX3 involvement in the etiopathogenetic mechanism of altered placentation as well as to define whether the main site of synthesis of PTX3 is the placental unit, the maternal–fetal interface or the systemic endothelium. This evidence might have significant clinical implications in the early diagnosis of preeclampsia.

PTX3 plasma and vaginal levels were also increased during pregnancy complicated by spontaneous preterm delivery and in particular in the cases of placental vasculopathy, diagnosed based on the presence of abnormalities of uteroplacental vessel segments, fibrinoid necrosis and atherosis, abruption, villus infarcts or fibrosis or hypovascularity [45].

PTX3 expression has also been recently identified in the human male genital tract, in the perivascular connective tissue, in endothelial cells and in the interstitium of accessory glands and in prostatic glandular cells and exudates. PTX3 was detected in the human semen, as soluble component of the seminal plasma, but also associate to immotile or non-progressive motile cells [46]. The biological function of semen PTX3 is unknown, so far. Potential roles could be related to innate resistance to pathogens in the genital tracts, apoptotic sperm clearance, control of complement attack in the female genital tract, immunoediting of paternal antigens in the female genital mucosa.

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3. Chemokines in reproductive immunology 

In each reproductive cycle leukocytes heavily infiltrate the periovulatory follicles, corpus luteum, and endometrium, and play a role in the preparation of the endometrium, its breakdown, and repair as the endometrial lining is rebuilt [47]. If pregnancy occurs, they are also involved in embryo implantation and placenta development, and in setting the balance between protecting the developing embryo and tolerating its hemiallogeneic tissues [47]. The predominant infiltrating leukocytes in first trimester gestational endometrium are monocyte/macrophages (20–25%) and uterine natural killer (uNK) cells (65–70%) [4]. Monocyte/macrophages are concentrated around the implantation site and near trophoblasts and are involved in regulating trophoblast invasion, whereas uNK cells are found around endometrial glands and vessels and are essential for proper tissue and vessel remodelling and normal development of the placenta [48]. uNK cell numeric increase and functional differentiation has also been described in the secretory phase of the cycle and has been ascribed to decidualization and cytokine (IL-15, IL-11, TGFβ) and chemokine expression in decidual tissues [48], [49]. uNK cells are also an important source of pro-inflammatory cytokines, as IL-12, IL-15, IL-18, IFNγ, chemokines, and angiogenic factors [4], [44], [48]. These mediators, in particular IFNγ and VEGF, are key molecules participating in spiral artery modification [4], [48]. It is still debated whether uNK cells are recruited from peripheral blood cells and undergo reprogramming of their receptor profile once exposed to the uterine microenvironment [50] or they are primary uterine cells [51]. uNK cell number declines after the first trimester and returns to the basal level at the end of pregnancy [4].

As in other tissues, leukocyte recruitment is mainly controlled by chemokines, a large family of chemotactic cytokines released by a variety of cell types, including endometrial cells, trophoblasts, blastocysts, uNK cells, monocytes/macrophages, and T cells. Chemokines also have a role in several other processes associated with the reproductive cycle and pregnancy, such as ovulation, menstruation, decidualization, and embryo implantation [49]. Finally, their unbalanced expression also contributes to pathological processes, including preterm delivery [52].

3.1. The chemokine decoy receptor D6 controls inflammatory chemokines 

Decoy receptors are defined as non-signalling receptors with ligand scavenging and signalling downregulation activity and represent a regulatory mechanism for different classes of immune mediators [53]. Recent in vitro and in vivo evidence indicate that three chemokine receptors structurally related to signaling receptors but unable to activate transduction events, the Duffy Antigen Receptor for Chemokines (DARC), D6 and CCX CKR, act as chemokine decoy receptors [54].

The best described chemokine decoy receptor is the D6 molecule, a seven transmembrane domain protein that shares 30–35% sequence identity to signalling chemokine receptors but does not support known signalling functions (e.g., as calcium fluxes and chemotaxis) [55], [56]. D6 recognizes most inflammatory CC chemokines and target them to degradation [56]. As previously described for other scavenger receptors including stabilin-1 and CD163, D6 cycles constitutively through both rapid (Rab4/5-dependent) and late (Rab11-dependent) cycling pathways, and after chemokine engagement improves its scavenging efficiency by increasing its membrane expression through acceleration of Rab11-dependent cycling pathway [57]. The relevance of the scavenger activity of D6 for appropriate control of the inflammatory response has been demonstrated in vivo using gene-targeted animals, which showed an exaggerated inflammatory response, with extensive leukocyte infiltration and necrosis, after subcutaneous injection of Freund's complete adjuvant [58] and skin application of phorbol esters [59].

3.2. Role of D6 in female fertility 

Other than lymphatic vessels of skin, gut, and lung [60], D6 is strongly expressed by invading trophoblast cells and on the apical side of syncytiotrophoblast cells [61] (Fig. 2). Experimental models of fetal loss associated with systemic inflammatory response have clearly highlighted a non-redundant role of D6 in placenta under inflammatory conditions [61]. Pregnant D6−/− mice showed a significant increase in fetal loss frequency as compared to wild type animals in the LPS fetal loss model, which mimics a clinical condition frequently associated with abortion and preterm delivery in humans. Levels of CC inflammatory chemokines were significantly higher in serum and placenta of D6−/− mice, similarly to what has previously been described in other experimental conditions [58], [59], and a significant increase in the number of macrophages and T lymphocytes infiltrating placenta in D6−/− mice as compared to wild type littermates were also demonstrated [61]. Monoclonal antibodies blocking inflammatory CC chemokines significantly reduced inflammation and fetal loss rate. A protective role of D6 was also evident in a second model based on the injection of antiphospholipid autoantibodies purified from patients affected by the antiphospholipid syndrome, a disorder characterized by recurrent thrombosis and fetal loss in the presence of pathogenic autoantibodies reacting against phospholipid binding proteins [62]. Infusion of human antiphospholipid autoantibodies induced fetal loss in pregnant mice by triggering a local inflammatory and necrotic process at the placenta level, with D6−/− animals susceptibility significantly increased when compared to wild type animals [61]. Finally, in a model of spontaneous fetal loss in swine, D6 was found expressed in endometrial epithelium, uterine glands, and trophoblast, and a notable loss in D6 immunoreactivity was observed in arresting versus viable littermate attachment sites [63]. These results highlight a previously unrecognized role of inflammatory chemokines in fetal abortion induced by inflammatory stimuli, and demonstrate that the absence of the scavenging function of D6 results in increased susceptibility to inflammation-driven fetal loss.

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  • Fig. 2 

    D6 expression in placenta. Immunohistochemistry on first trimester human placenta shows strong and diffuse D6 positivity on the apical side of syncytiotrophoblast cells (A) and on endothelium in decidua (B, arrows). Endometrial glands (B, **) are negative. Haematoxylin counterstaining, DAB (O.M. 10× in panel A, 40× in panel B).

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4. Concluding remarks 

Several evidence indicate that pregnancy is associated with a mild local and systemic inflammatory state in the mother, that dramatically increases in pregnancy disorders such as preeclampsia [5], [41]. Though the cause of the inflammatory response has not been precisely identified, it has been associated to the activation of the immune system as a consequence of fetal–maternal interaction. Several molecules of the innate immune system are involved in the control of trophoblast migration and differentiation, in leukocyte influx and activation in the implantation site, and in tuning the local immune responses to protect the fetus from infections as well as from maternal rejection. In this scenario, we provide evidence for a role of the long pentraxin PTX3 in normal female fertility, in processes which range from ECM assembly, angiogenesis, control of complement activation and inflammation, to removal of apoptotic cells; moreover, a potential role in pathologic conditions is suggested by its increased levels in various pregnancy disorders. Conversely, the chemokine scavenger receptor D6 has a non-redundant role in the fetus protection under inflammatory conditions. The relevance for human fertility of data obtained with PTX3 and D6 gene-targeted mice has to be proved and is presently under investigation.

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5. Conflict of interest 

The authors report no conflicts of interest.

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Acknowledgment 

This work is supported in part by funding under the European Commission (contracts: LSHM-CT-2004-512040: EMBIC; LSHB-CT-2005-518167: INNOCHEM; LSHG-CT-2005-005203: MUGEN), Ministero dell'Istruzione, Università e della Ricerca (FIRB RBIN04EKCX project), Telethon (grant n. GGP05095), CARIPLO Foundation (NOBEL project), and the University of Milan (FIRST project). The support of the Fondazione Humanitas per la Ricerca and Italian Association for Cancer Research is gratefully acknowledged.

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PII: S0143-4004(08)00199-9

doi:10.1016/j.placenta.2008.06.008

Placenta
Volume 29, Supplement 2 , Pages 129-134, October 2008

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