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Embryo implantation: A time for recalling and forwarding

  • Review / Physiology
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Chinese Science Bulletin

Abstract

The success of embryo implantation is a critical step towards further embryo development and pregnancy outcome. The observations and investigations on embryo implantation have been over a century. A huge body of knowledge has been accumulated in anatomy, histology, ultrastructure and hormonal regulation; as well as recently in depth information about molecular signaling pathways got from studies of genomic wide gene screening and specific gene deletion. The knowledge from basic research has also substantially helped to initiate and improve the Artificial Reproductive Technology (ART) in clinical applications. Now we’ve known that the normal embryo implantation involves the embryo’s development into an implantation-competent blastocyst and the synchronized transformation of uteri into a receptive stage. The interdependent relationship between the blastocyst and uterus involves complicated hormonal regulation and local paracrine, juxtacrine interactions. In this paper, we review some important historical findings regarding uterine receptivity and blastocyst activation, as well as some less discussed topics such as embryo spacing, embryo orientation. Further understandings on detailed mechanisms during the process of embryo implantation will help cure women infertility as well as develop new generation of non-steroids contraceptives.

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References

  1. Norwitz E R, Schust D J, Fisher S J. Implantation and the survival of early pregnancy. N Engl J Med, 2001, 345: 1400–1408

    Article  Google Scholar 

  2. Wilcox A J, Baird D D, Weinberg C R. Time of implantation of the conceptus and loss of pregnancy. N Engl J Med, 1999, 340: 1796–1799

    Article  Google Scholar 

  3. Dey S K. Reproductive biology: fatty link to fertility. Nature, 2005, 435: 34–35

    Article  Google Scholar 

  4. Song H, Lim H, Paria B C, et al. Cytosolic phospholipase A2alpha is crucial [correction of A2alpha deficiency is crucial] for ‘on-time’ embryo implantation that directs subsequent development. Development, 2002, 129(12): 2879–2889

    Google Scholar 

  5. Ye X, Hama K, Contos J J, et al. LPA3-mediated lysophosphatidic acid signalling in embryo implantation and spacing. Nature, 2005, 435: 104–108

    Article  Google Scholar 

  6. Doyle L L, Gates A H, Noyes R W. Asynchronous transfer of mouse ova. Fertil Steril, 1963, 14: 215–225

    Google Scholar 

  7. Dickmann Z N R. The fate of ova transferred into the uterus of the rat. J Reprod Fertil, 1960: 197–212

  8. Goto Y, Noda Y, Shiotani M, et al. The fate of embryos transferred into the uterus. J Assist Reprod Genet, 1993, 10: 197–201

    Article  Google Scholar 

  9. Paria B C, Huet-hudson Y M, Dey S K. Blastocyst’s state of activity determines the “window” of implantation in the receptive mouse uterus. Proc Natl Acad Sci USA, 1993, 90: 10159–10162

    Article  Google Scholar 

  10. Finn C A, Martin L. The control of implantation. J Reprod Fertil, 1974, 39: 195–206

    Google Scholar 

  11. Wang H, Dey S K. Roadmap to embryo implantation: clues from mouse models. Nat Rev Genet, 2006, 7: 185–199

    Article  Google Scholar 

  12. Finn C A, Martin L. Endocrine control of the timing of endometrial sensitivity to a decidual stimulus. Biol Reprod, 1972, 7: 82–86

    Google Scholar 

  13. Curtis H S, Goulding E H, Eddy E M, et al. Studies using the estrogen receptor alpha knockout uterus demonstrate that implantation but not decidualization-associated signaling is estrogen dependent. Biol Reprod, 2002, 67: 1268–1277

    Article  Google Scholar 

  14. Corner W M A A G W. PHYSIOLOGY OF THE CORPUS LUTEUM: III. Normal growth and implantation of embryos after very early ablation of the ovaries, under the influence of extracts of the corpus luteum. Am J Physiol, 1929, 88: 340–346

    Google Scholar 

  15. Tranguch S, Smith D F, Dey S K. Progesterone receptor requires a co-chaperone for signalling in uterine biology and implantation. Reprod Biomed Online, 2006, 13: 651–660

    Google Scholar 

  16. Lydon J P, Demayo F J, Conneely O M, et al. Reproductive phenotpes of the progesterone receptor null mutant mouse. J Steroid Biochem Mol Biol, 1996, 56(1–6 Spec No): 67–77

    Article  Google Scholar 

  17. Lydon J P, Demayo F J, Funk C R, et al. Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities. Genes Dev, 1995, 9: 2266–2278

    Article  Google Scholar 

  18. Dey S K, Lim H, Das S K, et al. Molecular cues to implantation. Endocr Rev, 2004, 25: 341–373

    Article  Google Scholar 

  19. Wang X, Matsumoto H, Zhao X, et al. Embryonic signals direct the formation of tight junctional permeability barrier in the decidualizing stroma during embryo implantation. J Cell Sci, 2004, 117: 53–62

    Article  Google Scholar 

  20. Collins M K, Tay C S, Erlebacher A. Dendritic cell entrapment within the pregnant uterus inhibits immune surveillance of the maternal/fetal interface in mice. J Clin Invest, 2009, 119: 2062–2073

    Google Scholar 

  21. Whitten W K. Endocrine studies on delayed implantation in lactating mice; role of the pituitary in implantation. J Endocrinol, 1958, 16: 435–440

    Article  Google Scholar 

  22. Ma W G, Song H, Das S K, et al. Estrogen is a critical determinant that specifies the duration of the window of uterine receptivity for implantation. Proc Natl Acad Sci USA, 2003, 100: 2963–2968

    Article  Google Scholar 

  23. Finn C A, Pope M D, Milligan S R. Timing of the window of uterine sensitivity to decidual stimuli in mice. Reprod Fertil Dev, 1992, 4: 565–571

    Article  Google Scholar 

  24. Das A, Mantena S R, Kannan A, et al. De novo synthesis of estrogen in pregnant uterus is critical for stromal decidualization and angiogenesis. Proc Natl Acad Sci USA, 2009, 106: 12542–12547

    Article  Google Scholar 

  25. Finn C A, Martin L. The role of the oestrogen secreted before oestrus in the preparation of the uterus for implantation in the mouse. J Endocrinol, 1970, 47: 431–438

    Article  Google Scholar 

  26. Wang X, Wang H, Matsumoto H, et al. Dual source and target of heparin-binding EGF-like growth factor during the onset of implantation in the hamster. Development, 2002, 129: 4125–4134

    Google Scholar 

  27. Reese J, Wang H, Ding T, et al. The hamster as a model for embryo implantation: Insights into a multifaceted process. Semin Cell Dev Biol, 2008, 19: 194–203

    Google Scholar 

  28. Stromstedt M, Keeney D S, Waterman M R, et al. Preimplantation mouse blastocysts fail to express CYP genes required for estrogen biosynthesis. Mol Reprod Dev, 1996, 43: 428–436

    Article  Google Scholar 

  29. Hetherington C M. Induction of deciduomata in the mouse by carbon dioxide. Nature, 1968, 219: 863–864

    Article  Google Scholar 

  30. Mclaren A. Stimulus and response during early pregnancy in the mouse. Nature, 1969, 221: 739–741

    Article  Google Scholar 

  31. Bany B M, Cross J C. Post-implantation mouse conceptuses produce paracrine signals that regulate the uterine endometrium undergoing decidualization. Dev Biol, 2006, 294: 445–456

    Article  Google Scholar 

  32. Kashiwagi A, Digirolamo C M, Kanda Y, et al. The postimplantation embryo differentially regulates endometrial gene expression and decidualization. Endocrinology, 2007, 148: 4173–4184

    Article  Google Scholar 

  33. Lefevre P, Campos D B, Murphy B D. Talk to me: the embryo dictates gene expression by the endometrium. Endocrinology, 2007, 148: 4170–4172

    Article  Google Scholar 

  34. Herington J L, Underwood T, Mcconaha M, et al. Paracrine signals from the mouse conceptus are not required for the normal progression of decidualization. Endocrinology, 2009, doi:10.1210/en. 2009-0036

  35. Stewart C L, Kaspar P, Brunet L J, et al. Blastocyst implantation depends on maternal expression of leukaemia inhibitory factor. Nature, 1992, 359: 76–79

    Article  Google Scholar 

  36. Robb L, Li R, Hartley L, et al. Infertility in female mice lacking the receptor for interleukin 11 is due to a defective uterine response to implantation. Nat Med, 1998, 4: 303–308

    Article  Google Scholar 

  37. Song H, Lim H, Das S K, et al. Dysregulation of EGF family of growth factors and COX-2 in the uterus during the preattachment and attachment reactions of the blastocyst with the luminal epithelium correlates with implantation failure in LIF-deficient mice. Mol Endocrinol, 2000, 14: 1147–1161

    Article  Google Scholar 

  38. Lim H, Paria B C, Das S K, et al. Multiple female reproductive failures in cyclooxygenase 2-deficient mice. Cell, 1997, 91: 197–208

    Article  Google Scholar 

  39. Lim H, Gupta R A, Ma W G, et al. Cyclo-oxygenase-2-derived prostacyclin mediates embryo implantation in the mouse via PPARdelta. Genes Dev, 1999, 13: 1561–1574

    Article  Google Scholar 

  40. Wang H, **e H, Sun X, et al. Stage-specific integration of maternal and embryonic peroxisome proliferator-activated receptor delta signaling is critical to pregnancy success. J Biol Chem, 2007, 282: 37770–37782

    Article  Google Scholar 

  41. **e H, Wang H, Tranguch S, et al. Maternal heparin-binding-EGF deficiency limits pregnancy success in mice. Proc Natl Acad Sci USA, 2007, 104: 18315–18320

    Article  Google Scholar 

  42. Laws M J, Taylor R N, Sidell N, et al. Gap junction communication between uterine stromal cells plays a critical role in pregnancy-associated neovascularization and embryo survival. Development, 2008, 135: 2659–2668

    Article  Google Scholar 

  43. Plaks V, Birnberg T, Berkutzki T, et al. Uterine DCs are crucial for decidua formation during embryo implantation in mice. J Clin Invest, 2008, 118: 3954–3965

    Google Scholar 

  44. Lee K, Jeong J, Kwak I, et al. Indian hedgehog is a major mediator of progesterone signaling in the mouse uterus. Nat Genet, 2006, 38: 1204–1209

    Article  Google Scholar 

  45. Lee K Y, Jeong J W, Wang J, et al. Bmp2 is critical for the murine uterine decidual response. Mol Cell Biol, 2007, 27: 5468–5478

    Article  Google Scholar 

  46. Li Q, Kannan A, Wang W, et al. Bone morphogenetic protein 2 functions via a conserved signaling pathway involving Wnt4 to regulate uterine decidualization in the mouse and the human. J Biol Chem, 2007, 282: 31725–31732

    Article  Google Scholar 

  47. Carson D D, Bagchi I, Dey S K, et al. Embryo implantation. Dev Biol, 2000, 223: 217–237

    Article  Google Scholar 

  48. Paria B C, Reese J, Das S K, et al. Deciphering the cross-talk of implantation: advances and challenges. Science, 2002, 296: 2185–2188

    Article  Google Scholar 

  49. Lee K Y, Jeong J W, Tsai S Y, et al. Mouse models of implantation. Trends Endocrinol Metab, 2007, 18: 234–239

    Article  Google Scholar 

  50. Hou Q, Paria B C, Mui C, et al. Immunolocalization of estrogen receptor protein in the mouse blastocyst during normal and delayed implantation. Proc Natl Acad Sci USA, 1996, 93: 2376–2381

    Article  Google Scholar 

  51. Paria B C, Lim H, Wang X N, et al. Coordination of differential effects of primary estrogen and catecholestrogen on two distinct targets mediates embryo implantation in the mouse. Endocrinology, 1998, 139: 5235–5246

    Article  Google Scholar 

  52. Hamatani T, Daikoku T, Wang H, et al. Global gene expression analysis identifies molecular pathways distinguishing blastocyst dormancy and activation. Proc Natl Acad Sci USA, 2004, 101: 10326–10331

    Article  Google Scholar 

  53. Wang H, Matsumoto H, Guo Y, et al. Differential G protein-coupled cannabinoid receptor signaling by anandamide directs blastocyst activation for implantation. Proc Natl Acad Sci USA, 2003, 100: 14914–14919

    Article  Google Scholar 

  54. Das S K, Wang X N, Paria B C, et al. Heparin-binding EGF-like growth factor gene is induced in the mouse uterus temporally by the blastocyst solely at the site of its apposition: a possible ligand for interaction with blastocyst EGF-receptor in implantation. Development, 1994, 120: 1071–1083

    Google Scholar 

  55. Paria B C, Ma W, Tan J, et al. Cellular and molecular responses of the uterus to embryo implantation can be elicited by locally applied growth factors. Proc Natl Acad Sci USA, 2001, 98: 1047–1052

    Article  Google Scholar 

  56. Paria B C, Das S K, Andrews G K, et al. Expression of the epidermal growth factor receptor gene is regulated in mouse blastocysts during delayed implantation. Proc Natl Acad Sci USA, 1993, 90: 55–59

    Article  Google Scholar 

  57. Wang J, Mayernik L, Schultz J F, et al. Acceleration of trophoblast differentiation by heparin-binding EGF-like growth factor is dependent on the stage-specific activation of calcium influx by ErbB receptors in develo** mouse blastocysts. Development, 2000, 127: 33–44

    Google Scholar 

  58. Paria B C, Elenius K, Klagsbrun M, et al. Heparin-binding EGF-like growth factor interacts with mouse blastocysts independently of ErbB1: A possible role for heparan sulfate proteoglycans and ErbB4 in blastocyst implantation. Development, 1999, 126: 1997–2005

    Google Scholar 

  59. Das S K, Chakraborty I, Paria B C, et al. Amphiregulin is an implantation-specific and progesterone-regulated gene in the mouse uterus. Mol Endocrinol, 1995, 9: 691–705

    Article  Google Scholar 

  60. Guo Y, Wang H, Okamoto Y, et al. N-acylphosphatidylethanolamine-hydrolyzing phospholipase D is an important determinant of uterine anandamide levels during implantation. J Biol Chem, 2005, 280: 23429–23432

    Article  Google Scholar 

  61. Liu W M, Duan E K, Cao Y J. Effects of anandamide on embryo implantation in the mouse. Life Sci, 2002, 71: 1623–1632

    Article  Google Scholar 

  62. **e H, Tranguch S, Jia X, et al. Inactivation of nuclear Wnt-beta-catenin signaling limits blastocyst competency for implantation. Development, 2008, 135: 717–727

    Article  Google Scholar 

  63. Ueda O, Yorozu K, Kamada N, et al. Possible expansion of “Window of Implantation” in pseudopregnant mice: time of implantation of embryos at different stages of development transferred into the same recipient. Biol Reprod, 2003, 69: 1085–1090

    Article  Google Scholar 

  64. Shiotani M, Noda Y, Mori T. Embryo-dependent induction of uterine receptivity assessed by an in vitro model of implantation in mice. Biol Reprod, 1993, 49: 794–801

    Article  Google Scholar 

  65. Wakuda K, Takakura K, Nakanishi K, et al. Embryo-dependent induction of embryo receptivity in the mouse endometrium. J Reprod Fertil, 1999, 115: 315–324

    Article  Google Scholar 

  66. Matorras R, Matorras F, Mendoza R, et al. The implantation of every embryo facilitates the chances of the remaining embryos to implant in an IVF programme: a mathematical model to predict pregnancy and multiple pregnancy rates. Hum Reprod, 2005, 20: 2923–2931

    Article  Google Scholar 

  67. Van M A, Fiddelers A A, Janssen J M, et al. In unselected patients, elective single embryo transfer prevents all multiples, but results in significantly lower pregnancy rates compared with double embryo transfer: A randomized controlled trial. Hum Reprod, 2006, 21: 338–343

    Google Scholar 

  68. Wimsatt W A. Some comparative aspects of implantation. Biol Reprod, 1975, 12: 1–40

    Article  Google Scholar 

  69. Mclaren A, Michie D. The spacing of implantations in the mouse uterus. Mem Soc Endocr, 1959, 6: 65–75

    Google Scholar 

  70. Restall B J, Bindon B M. The timing and variation of pre-implantation events in the mouse. J Reprod Fertil, 1971, 24: 423–426

    Article  Google Scholar 

  71. Wellstead J R, Bruce N W, Rahima A. Effects of indomethacin on spacing of conceptuses within the uterine horn and on fetal and placental growth in the rat. Anat Rec, 1989, 225: 101–105

    Article  Google Scholar 

  72. Kinoshita K, Satoh K, Ishihara O, et al. Involvement of prostaglandins in implantation in the pregnant mouse. Adv Prostaglandin Thromboxane Leukot Res, 1985, 15: 605–607

    Google Scholar 

  73. Hama K, Aoki J, Inoue A, et al. Embryo spacing and implantation timing are differentially regulated by LPA3-mediated lysophosphatidic acid signaling in mice. Biol Reprod, 2007, 77: 954–959

    Article  Google Scholar 

  74. Pusey J, Kelly W A, Bradshaw J M, et al. Myometrial activity and the distribution of blastocysts in the uterus of the rat: Interference by relaxin. Biol Reprod, 1980, 23: 394–397

    Article  Google Scholar 

  75. Yoshinaga K, Rice C, Krenn J, et al. Effects of nicotine on early pregnancy in the rat. Biol Reprod, 1979, 20: 294–303

    Article  Google Scholar 

  76. Legrand C, Banuelos-nevarez A, Rigolot C, et al. Comparative effects of 6-hydroxydopamine and alpha-adrenoceptor antagonists on intrauterine migration and spacing of blastocysts in the rat. J Reprod Fertil, 1987, 81: 51–58

    Article  Google Scholar 

  77. Alden R H. Implantation of the rat egg. I. Experimental alteration of uterine polarity. J Exp Zool, 1945, 100: 229–235

    Article  Google Scholar 

  78. Yang Z M, Das S K, Wang J, et al. Potential sites of prostaglandin actions in the periimplantation mouse uterus: differential expression and regulation of prostaglandin receptor genes. Biol Reprod, 1997, 56: 368–379

    Article  Google Scholar 

  79. Haffner-krausz R, Gorivodsky M, Chen Y, et al. Expression of Fgfr2 in the early mouse embryo indicates its involvement in preimplantation development. Mech Dev, 1999, 85: 167–172

    Article  Google Scholar 

  80. Pinborg A, Lidegaard O, Andersen A N. The vanishing twin: a major determinant of infant outcome in IVF singleton births. Br J Hosp Med (Lond), 2006, 67: 417–420

    Google Scholar 

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Correspondence to EnKui Duan.

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Supported by the National Key Basic Research and Development Program of China (Grant No. 2006CB944006) and National Natural Science Foundation of China (Grant No. 30770819)

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Chen, Q., Peng, H., Zhang, Y. et al. Embryo implantation: A time for recalling and forwarding. Chin. Sci. Bull. 54, 4083–4093 (2009). https://doi.org/10.1007/s11434-009-0631-3

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  • DOI: https://doi.org/10.1007/s11434-009-0631-3

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