Embryo-maternal signalling: how the embryo starts talking to its mother to accomplish implantation.

The process of implantation and trophoblast invasion is currently considered as the most limiting factor for the establishment of pregnancy. Molecular interactions at the embryo-maternal interface during the time of adhesion and subsequent invasion are crucial to the process of embryonic implantation. Both partners, the mother as well as the embryo, play equal roles in the embryo-maternal dialogue, the embryonic part being the main topic in this study. Investigations of the proteins in the extra-embryonic matrices (i.e. zona pellucida) indicate that the embryo participates intensively in this early embryo-maternal signalling. One unique feature during implantation process of primate embryos is the release of chorionic gonadotrophin, which seems to influence endometrial activity by two different mechanisms: (i) luteotrophic activity with increasing progesterone release and (ii) a direct action on the endometrium. Furthermore, embryonic interleukin-1beta may be involved in embryo-maternal signalling. Other significant signals in this interaction are most likely leukaemia inhibitory factor (LIF) and colony-stimulating factor (CSF), which stimulate matrix metalloproteinase (MMP)/insulin-like growth factor binding protein-1 (IGFBP-1) activity and the insulin-like growth factor (IGF) system, which is modulated by embryonic IGFBP-3. Similar significances are discussed for uteroglobin and haptoglobin. Finally, the phenomenon of maternal immunological tolerance, triggered by the presence of the early embryo, is fundamental to the understanding of implantation and trophoblast invasion. A tightly regulated balance between activated and inactivated T cells at the implantation site may control the beginning of adequate trophoblast invasion and also limit this invasion to a tolerable extent for the maternal system, consequently ensuring a biologically healthy haemo-chorial placenta.

[1]  F. Rojas,et al.  Status of hCG/LH receptor and G proteins in human endometrium during artificial cycles of hormone replacement therapy. , 1995 .

[2]  S. Han,et al.  Treatment of human endometrial stromal cells with chorionic gonadotropin promotes their morphological and functional differentiation into decidua , 1999, Molecular and Cellular Endocrinology.

[3]  P. Lala,et al.  Insulin-Like Growth Factor-Binding Protein 1 Stimulates Human Trophoblast Migration by Signaling through α5β1 Integrin via Mitogen-Activated Protein Kinase Pathway1 , 2001 .

[4]  H. M. Beier,et al.  Significance of maternal uterine proteins in the establishment of pregnancy. , 1978, Ciba Foundation symposium.

[5]  R. Lambert,et al.  Immunosuppressive effects of rabbit blastocoelic fluid and embryo culture medium. , 1988, Journal of reproductive immunology.

[6]  R. Steinman,et al.  The Induction of Tolerance by Dendritic Cells That Have Captured Apoptotic Cells , 2000, The Journal of experimental medicine.

[7]  A. Fazleabas,et al.  The role of chorionic gonadotropin (CG) in blastocyst implantation. , 2001, Archives of medical research.

[8]  S. Han,et al.  Up-regulation of cyclooxygenase-2 gene expression by chorionic gonadotropin during the differentiation of human endometrial stromal cells into decidua. , 1996, Endocrinology.

[9]  S. Gupta,et al.  The HSD‐hCG Vaccine Prevents Pregnancy in Women: Feasibility Study of a Reversible Safe Contraceptive Vaccine , 1997, American journal of reproductive immunology.

[10]  H. Beier,et al.  Effects of trophoblast invasion on the distribution of leukocytes in uterine and tubal implantation sites. , 2001, Fertility and sterility.

[11]  N. Bottini,et al.  Haptoglobin genotype and natural fertility in humans. , 1999, Fertility and sterility.

[12]  J. Kim,et al.  Implantation in the baboon: endometrial responses. , 1999, Seminars in reproductive endocrinology.

[13]  C. Conover,et al.  Factors regulating insulin-like growth factor-binding protein-3 binding, processing, and potentiation of insulin-like growth factor action. , 1996, Endocrinology.

[14]  J. Hodges,et al.  Early secretion of chorionic gonadotrophin by marmoset embryos in vivo and in vitro. , 1988, The Journal of endocrinology.

[15]  A. Mercader,et al.  The Interleukin‐1 System and Human Implantation , 1997, American journal of reproductive immunology.

[16]  L. Jarett,et al.  Mouse preimplantation embryos exhibit receptor-mediated binding and transcytosis of maternal insulin-like growth factor I. , 1993, Biology of reproduction.

[17]  H. M. Beier,et al.  Cytokine microenvironments in human first trimester decidua are dependent on trophoblast cells. , 2003, Fertility and sterility.

[18]  W. C. Duncan,et al.  The human corpus luteum: remodelling during luteolysis and maternal recognition of pregnancy. , 2000, Reviews of reproduction.

[19]  C. Simón,et al.  Molecular interactions between embryo and uterus in the adhesion phase of human implantation. , 1998, Human reproduction.

[20]  Gonadotropins and the uterus: is there a gonad-independent pathway? , 2001 .

[21]  N. Narita,et al.  Expression of activation antigens CD69, HLA-DR, interleukin-2 receptor-alpha (IL-2R alpha) and IL-2R beta on T cells of human decidua at an early stage of pregnancy. , 1992, Immunology.

[22]  B. Croy,et al.  Engraftment of Bone Marrow from Severe Combined Immunodeficient (SCID) Mice Reverses the Reproductive Deficits in Natural Killer Cell–deficient tgε26 Mice , 1998, The Journal of experimental medicine.

[23]  C. Weinberg,et al.  Hormonal profiles of natural conception cycles ending in early, unrecognized pregnancy loss. , 1991, The Journal of clinical endocrinology and metabolism.

[24]  Stephen K. Smith,et al.  Stage-specific expression of cytokine and receptor messenger ribonucleic acids in human preimplantation embryos. , 1995, Biology of reproduction.

[25]  S. Fujii,et al.  Human peripheral blood mononuclear cells (PBMC) in early pregnancy promote embryo invasion in vitro: HCG enhances the effects of PBMC. , 2002, Human reproduction.

[26]  J. Hearn.  Immunization against pregnancy , 1976, Proceedings of the Royal Society of London. Series B. Biological Sciences.

[27]  H. M. Beier,et al.  Early Embryonic Coats: Morphology, Function, Practical Applications , 2000, Cells Tissues Organs.

[28]  I. Natali,et al.  Production of IL‐4 and leukemia inhibitory factor by T cells of the cumulus oophorus: a favorable microenvironment for pre‐implantation embryo development , 2001, European journal of immunology.

[29]  V. Winfrey,et al.  A haptoglobin-like glycoprotein is produced by implantation-stage rabbit endometrium. , 1996, Biology of reproduction.

[30]  H. Matsuo,et al.  Biology of human trophoblast , 1998, International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics.

[31]  J. Geraedts,et al.  Conception to ongoing pregnancy: the 'black box' of early pregnancy loss. , 2002, Human reproduction update.

[32]  G. Coukos,et al.  Corticotropin-releasing hormone promotes blastocyst implantation and early maternal tolerance , 2001, Nature Immunology.

[33]  R. Akhurst,et al.  Chorionic gonadotrophin-beta mRNA, a trophoblast marker, is expressed in human 8-cell embryos derived from tripronucleate zygotes. , 1988, Human reproduction.

[34]  S. Fujii,et al.  Peripheral blood mononuclear cells in early pregnancy promote invasion of human choriocarcinoma cell line, BeWo cells. , 2002, Human reproduction.

[35]  E. Terasawa,et al.  The secretion of gonadotrophin-releasing hormone by peri-implantation embryos of the rhesus monkey: comparison with the secretion of chorionic gonadotrophin. , 1994, Human reproduction.

[36]  A. Herrler,et al.  Proteins in the extraembryonic matrix of preimplantation rabbit embryos , 2002, Anatomy and Embryology.

[37]  A. Abbas,et al.  Homeostasis and self-tolerance in the immune system: turning lymphocytes off. , 1998, Science.

[38]  C. Weinberg,et al.  Time of implantation of the conceptus and loss of pregnancy. , 1999, The New England journal of medicine.

[39]  R. Edwards,et al.  Human chorionic gonadotropin secreted by preimplantation embryos cultured in vitro. , 1984, Science.

[40]  C. Warner,et al.  Killing of mouse blastocyst stage embryos by cytotoxic T lymphocytes directed to major histocompatibility complex antigens. , 1987, Journal of Immunology.

[41]  N. Chegini,et al.  The presence of gonadotropin receptors in nonpregnant human uterus, human placenta, fetal membranes, and decidua. , 1990, The Journal of clinical endocrinology and metabolism.

[42]  G. Chaouat,et al.  New insights into maternal-fetal interactions at implantation. , 2001, Reproductive biomedicine online.

[43]  R. Lambert,et al.  PGE2, but not TGF beta 2, in rabbit blastocoelic fluid regulates the cytotoxic activities of NK and LAK cells. , 1997, Journal of reproductive immunology.

[44]  A. Moffett-King.  Natural killer cells and pregnancy , 2002, Nature Reviews Immunology.

[45]  H. M. Beier,et al.  Effect of in vitro culture on the dynamics of uteroglobin distribution in rabbit blastocysts , 2004, Anatomy and Embryology.

[46]  H. M. Beier,et al.  Uteroglobin Expression and Release in the Human Endometrium , 2000, Annals of the New York Academy of Sciences.

[47]  Y. S. Yang,et al.  The expression of killer cell inhibitory receptors on natural killer cells and activation status of CD4+ and CD8+ T cells in the decidua of normal and abnormal early pregnancies. , 1999, Human immunology.

[48]  J. Hearn.  Embryo implantation and embryonic stem cell development in primates. , 2001, Reproduction, fertility, and development.

[49]  W. Thatcher,et al.  Maternal recognition of pregnancy. , 2019, Journal of reproduction and fertility. Supplement.

[50]  A. Pilon.  Rationale for the Development of Recombinant Human CC10 as a Therapeutic for Inflammatory and Fibrotic Disease , 2000, Annals of the New York Academy of Sciences.

[51]  H. M. Beier,et al.  Full-Length Complementary DNA and the Derived Amino Acid Sequence of Horse Uteroglobin1 , 2002, Biology of reproduction.

[52]  C. Kirchner,et al.  Uteroglobin in the developing rabbit conceptus in vivo and in vitro , 2004, Anatomy and Embryology.

[53]  M. Piccinni,et al.  Defective production of LIF, M-CSF and Th2-type cytokines by T cells at fetomaternal interface is associated with pregnancy loss. , 2001, Journal of reproductive immunology.

[54]  C. Dubois,et al.  TGFβ2 in Rabbit Blastocoelic Fluid Regulates CD4 Membrane Expression: Possible Role in the Success of Gestation , 1997, American journal of reproductive immunology.

[55]  R. Lambert,et al.  TGF‐β2 and PGE2 in Rabbit Blastocoelic Fluid Can Modulate GM‐CSF Production by Human Lymphocytes , 1997, American journal of reproductive immunology.

[56]  H. Carp,et al.  Cytokine expression in the uterus of mice with pregnancy loss: effect of maternal immunopotentiation with GM-CSF. , 2002, Reproduction.

[57]  J. Levine,et al.  The role of apoptosis in autoimmunity: immunogen, antigen, and accelerant. , 1999, Seminars in nephrology.

[58]  D. Valbuena,et al.  Interleukin-1 receptor antagonist prevents embryonic implantation by a direct effect on the endometrial epithelium. , 1998, Fertility and sterility.

[59]  A. Arıcı,et al.  Modulation of leukemia inhibitory factor gene expression and protein biosynthesis in human endometrium. , 1995, The Journal of clinical endocrinology and metabolism.

[60]  G. Schultz,et al.  Insulin-like growth factor binding proteins are transcribed by preimplantation mouse embryos. , 1994, Endocrinology.

[61]  L. Wildt,et al.  On the Role of Human Chorionic Gonadotropin (hCG) in the Embryo-Endometrial Microenvironment: Implications for Differentiation and Implantation , 2001, Seminars in reproductive medicine.

[62]  H. M. Beier,et al.  Binding of IGF-I to preimplantation rabbit embryos and their coats. , 1997, Theriogenology.

[63]  P. Bischof.  Endocrine, paracrine and autocrine regulation of trophoblastic metalloproteinases. , 2001, Early pregnancy.

[64]  J. Davoust,et al.  Processing of engulfed apoptotic bodies yields T cell epitopes. , 1997, Journal of immunology.

[65]  B. V. Van Voorhis,et al.  Messenger ribonucleic acid for the gonadal luteinizing hormone/human chorionic gonadotropin receptor is not present in human endometrium. , 1999, Fertility and sterility.

[66]  H. Beier,et al.  Specific secretory protein of the female genital tract. , 1973, Acta endocrinologica. Supplementum.

[67]  B. Huppertz,et al.  Expression of a cytokeratin 18 neo-epitope is a specific marker for trophoblast apoptosis in human placenta. , 2001, Placenta.

[68]  H. M. Beier,et al.  Uteroglobin: a hormone-sensitive endometrial protein involved in blastocyst development. , 1968, Biochimica et biophysica acta.

[69]  M. Kane,et al.  Peptide growth factors and preimplantation development. , 1997, Human reproduction update.

[70]  R. Winston,et al.  Anti-Apoptotic Action of Insulin-Like Growth Factor-I During Human Preimplantation Embryo Development , 2000, Biology of reproduction.

[71]  H. M. Beier,et al.  Insulin and insulin-like growth factor-I promote rabbit blastocyst development and prevent apoptosis. , 1998, Biology of reproduction.

[72]  J. Ceuppens,et al.  Identification of haptoglobin as an alternative ligand for CD11b/CD18. , 1996, Journal of immunology.

[73]  L. Wildt,et al.  Novel insights into human endometrial paracrinology and embryo-maternal communication by intrauterine microdialysis. , 1998, Human reproduction update.

[74]  M. Green,et al.  Proteolysis of insulin-like growth factor-binding proteins (IGFBPs) within the pig uterine lumen associated with peri-implantation conceptus development. , 1998, Journal of reproduction and fertility.

[75]  R. Lambert,et al.  CD8 Membrane Expression Is Down‐regulated by Transforming Growth Factor (TGF)‐β1, TGF‐β2, and Prostaglandin E2 , 1999 .

[76]  W. Dobryszycka,et al.  Biological functions of haptoglobin--new pieces to an old puzzle. , 1997, European journal of clinical chemistry and clinical biochemistry : journal of the Forum of European Clinical Chemistry Societies.

[77]  J. Pell,et al.  Horse Conceptuses Secrete Insulin-Like Growth Factor-Binding Protein 31 , 2000, Biology of reproduction.

[78]  D. Vandermolen,et al.  Human Endometrial Expression of Granulocyte Colony‐Stimulating Factor (G‐CSF) and Its Receptor, Stimulation of Endometrial G‐CSF Production by Interleukin‐1β, and G‐CSF Inhibition of Choriocarcinoma Cell Proliferation , 1996, American journal of reproductive immunology.

[79]  A. Fazleabas,et al.  Interleukin-1β Induces the Expression of Insulin-Like Growth Factor Binding Protein-1 during Decidualization in the Primate* *This work was supported by NIH Grant HD-36759. , 2000, Endocrinology.