Skip to main content
SpringerLink
Log in

In Vitro Models for the Study of Early Human Embryo-Endometrium Interactions

  • Reviews
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

The molecular interactions at the embryo-endometrial interface during the period of blastocyst adhesion and subsequent invasion into the endometrial stroma are not fully understood. Current knowledge is primarily based on evidence from implantation studies in the mouse. The degree to which data derived from animal studies mirror human implantation is limited. The ethical and technical challenges studying implantation in the human can partly be overcome by designing in vitro models of embryo-endometrium interactions. In this review, the principal models in current use are described. Basic models using tissue explants and monolayers are distinguished from complex models using multilayer isolated cells, and embryo-endometrium coculture systems used therapeutically. Although there are limitations to current approaches, a number of research questions that could be addressed using these techniques are identified.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Macklon NS, Geraedts JP, Fauser BC. Conception to ongoing pregnancy: the ‘black box’ of early pregnancy loss. Hum Reprod Update. 2002;8(4):333–343.

    Article  CAS  PubMed  Google Scholar 

  2. Chen HW, Chen JJ, Yu SL, et al. Transcriptome analysis in blastocyst hatching by cDNA microarray. Hum Reprod. 2005;20(9):2492–2501.

    Article  CAS  PubMed  Google Scholar 

  3. Hamatani T, Ko MS, Yamada M, et al. Global gene expression profiling of preimplantation embryos. Hum Cell. 2006; 19(3):98–117.

    Article  PubMed  Google Scholar 

  4. Wang H, Dey SK. Roadmap to embryo implantation: clues from mouse models. Nat Rev Genet. 2006;7(3):185–199.

    Article  CAS  PubMed  Google Scholar 

  5. FAWCETT DW. The development of mouse ova under the capsule of the kidney. Anat Rec. 1950;108(1):71–91.

    Article  CAS  PubMed  Google Scholar 

  6. Harper MJ. The implantation window. Baillieres Clin Obstet Gynaecol. 1992;6(2):351–371.

    Article  CAS  PubMed  Google Scholar 

  7. Wilcox AJ, Baird DD, Weinberg CR. Time of implantation of the conceptus and loss of pregnancy. N Engl J Med. 1999; 340(23):1796–1799.

    Article  CAS  PubMed  Google Scholar 

  8. Lessey BA. Endometrial receptivity and the window of implantation. Baillieres Best.Pract Res Clin Obstet Gynaecol. 2000;14(5):775–788.

    Article  CAS  PubMed  Google Scholar 

  9. Horcajadas JA, az-Gimeno P, Pellicer A, Simon C. Uterine receptivity and the ramifications of ovarian stimulation on endometrial function. Semin Reprod Med. 2007;25(6):454–460.

    Article  PubMed  Google Scholar 

  10. Talbi S, Hamilton AE, Vo KC, et al. Molecular phenotyping of human endometrium distinguishes menstrual cycle phases and underlying biological processes in normo-ovulatory women. Endocrinology. 2006;147(3):1097–1121.

    Article  CAS  PubMed  Google Scholar 

  11. Diedrich K, Fauser BC, Devroey P, Griesinger G. The role of the endometrium and embryo in human implantation. Hum Reprod Update. 2007;13(4):365–377.

    Article  CAS  PubMed  Google Scholar 

  12. Boomsma CM, Kavelaars A, Eijkemans JC, et al. Cytokine profiling in endometrial secretions: a non-invasive window on endometrial receptivity. Reprod Biomed Online. 2009;18(1):85–94.

    Article  CAS  PubMed  Google Scholar 

  13. Boomsma CM, Kavelaars A, Eijkemans JC, et al. Analysis of the endometrial secretion cytokine profile to predict pregnancy in in-vitro fertilization. Hum Reprod. 2009. [Epub ahead of print.]

  14. van der Gaast MH, Classen-Linke I, Krusche CA, et al. Impact of ovarian stimulation on mid-luteal endometrial tissue and secretion markers of receptivity. Reprod Biomed Online. 2008;17(4):553–563.

    Article  PubMed  Google Scholar 

  15. van der Gaast MH, Macklon NS, Beier-Hellwig K, et al. The feasibility of a less invasive method to assess endometrial maturation—comparison of simultaneously obtained uterine secretion and tissue biopsy. BJOG. 2009;116(2): 304–312.

    Article  PubMed  Google Scholar 

  16. Scott R, Seli E, Miller K, Sakkas D, Scott K, Burns DH. Non-invasive metabolomic profiling of human embryo culture media using Raman spectroscopy predicts embryonic reproductive potential: a prospective blinded pilot study. Fertil Steril. 2008;90(1):77–83.

    Article  PubMed  Google Scholar 

  17. Munne S, Magli C, Cohen J, et al. Positive outcome after pre-implantation diagnosis of aneuploidy in human embryos. Hum Reprod. 1999;14(9):2191–2199.

    Article  CAS  PubMed  Google Scholar 

  18. Munne S, Bahce M, Sandalinas M, et al. Differences in chromosome susceptibility to aneuploidy and survival to first trimester. Reprod Biomed Online. 2004;8(1):81–90.

    Article  PubMed  Google Scholar 

  19. Stewart CL, Kaspar P, Brunet LJ, et al. Blastocyst implantation depends on maternal expression of leukaemia inhibitory factor. Nature. 1992;359(6390):76–79.

    Article  CAS  PubMed  Google Scholar 

  20. Cullinan EB, Abbondanzo SJ, Anderson PS, Pollard JW, Lessey BA, Stewart CL. Leukemia inhibitory factor (LIF) and LIF receptor expression in human endometrium suggests a potential autocrine/paracrine function in regulating embryo implantation. Proc Natl Acad Sci U S A. 1996;93(7):3115–3120.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Nyachieo A, Chai DC, Deprest J, Mwenda JM, D’Hooghe TM. The baboon as a research model for the study of endometrial biology, uterine receptivity and embryo implantation. Gynecol Obstet Invest. 2007;64(3):149–155.

    Article  PubMed  Google Scholar 

  22. GLENISTER TW. Observations on the behaviour in organ culture of rabbit trophoblast from implanting blastocysts and early placentae. J Anat. 1961;95:474–484.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Salomon DS, Sherman MI. Implantation and invasiveness of mouse blastocysts on uterine monolayers. Exp Cell Res. 1975;90(2):261–268.

    Article  CAS  PubMed  Google Scholar 

  24. Sherman MI, Shalgi R, Rizzino A, Sellens MH, Gay S, Gay R. Changes in the surface of the mouse blastocyst at implantation. Ciba Found.Symp. 1978(64):33–52.

  25. Steptoe PC, Edwards RG. Birth after the reimplantation of a human embryo. Lancet. 1978;2(8085):366.

    Article  CAS  PubMed  Google Scholar 

  26. Hertig AT, Rock J. Searching for early fertilized human ova. Gynecol.Invest. 1973;4(3):121–139.

    Article  CAS  PubMed  Google Scholar 

  27. Edwards RG. Test-tube babies, 1981. Nature. 1981; 293(5830):253–256.

    Article  CAS  PubMed  Google Scholar 

  28. Landgren BM, Johannisson E, Stavreus-Evers A, Hamberger L, Eriksson H. A new method to study the process of implantation of a human blastocyst in vitro. Fertil Steril. 1996;65(5):1067–1070.

    Article  CAS  PubMed  Google Scholar 

  29. Kliman HJ, Feinberg RF, Haimowitz JE. Human trophoblast-endometrial interactions in an in vitro suspension culture system. Placenta. 1990;11(4):349–367.

    Article  CAS  PubMed  Google Scholar 

  30. Popovici RM, Kao LC, Giudice LC. Discovery of new inducible genes in in vitro decidualized human endometrial stromal cells using microarray technology. Endocrinology. 2000;141(9):3510–3513.

    Article  CAS  PubMed  Google Scholar 

  31. Cetin I, Cozzi V, Pasqualini F, et al. Elevated maternal levels of the long pentraxin 3 (PTX3) in preeclampsia and intrauterine growth restriction. Am J Obstet Gynecol. 2006;194(5):1347–1353.

    Article  CAS  PubMed  Google Scholar 

  32. Popovici RM, Betzler NK, Krause MS, et al. Gene expression profiling of human endometrial-trophoblast interaction in a coculture model. Endocrinology. 2006;147(12):5662–5675.

    Article  CAS  PubMed  Google Scholar 

  33. Carver J, Martin K, Spyropoulou I, Barlow D, Sargent I, Mardon H. An in-vitro model for stromal invasion during implantation of the human blastocyst. Hum Reprod. 2003;18(2):283–290.

    Article  CAS  PubMed  Google Scholar 

  34. Grewal S, Carver JG, Ridley AJ, Mardon HJ. Implantation of the human embryo requires Rac1-dependent endometrial stromal cell migration. Proc Natl Acad Sci U S A. 2008;105(42):16189–16194.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Gao Y, Dickerson JB, Guo F, Zheng J, Zheng Y. Rational design and characterization of a Rac GTPase-specific small molecule inhibitor. Proc Natl Acad Sci U S A. 2004;101(20):7618–7623.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Wetzels AM, Bastiaans BA, Hendriks JC, et al. The effects of co-culture with human fibroblasts on human embryo development in vitro and implantation. Hum Reprod. 1998;13(5):1325–1330.

    Article  CAS  PubMed  Google Scholar 

  37. Wetzels AM, Punt-Van der Zalm AP, Bastiaans BA, et al. The effects of human skin fibroblast monolayers on human sperm motility and mouse zygote development. Hum Reprod. 1992;7(6):852–856.

    Article  CAS  PubMed  Google Scholar 

  38. Wetzels AM, Van der AI, Bastiaans BA, et al. Sperm functional changes and fertilization in vitro in co-culture with human skin fibroblasts. Hum Reprod. 1995;10(1):137–141.

    Article  CAS  PubMed  Google Scholar 

  39. Pierro E, Minici F, Alesiani O, et al. Stromal-epithelial interactions modulate estrogen responsiveness in normal human endometrium. Biol Reprod. 2001;64(3):831–838.

    Article  CAS  PubMed  Google Scholar 

  40. Mahfoudi A, Fauconnet S, Bride J, et al. Serum-free culture of stromal and functionally polarized epithelial cells of guinea-pig endometrium: a potential model for the study of epithelial-stromal paracrine interactions. Biol Cell. 1992;74(3):255–265.

    Article  CAS  PubMed  Google Scholar 

  41. Blauer M, Heinonen PK, Martikainen PM, Tomas E, Ylikomi T. A novel organotypic culture model for normal human endometrium: regulation of epithelial cell proliferation by estradiol and medroxyprogesterone acetate. Hum Reprod. 2005;20(4):864–871.

    Article  CAS  PubMed  Google Scholar 

  42. Bentin-Ley U, Pedersen B, Lindenberg S, Larsen JF, Hamberger L, Horn T. Isolation and culture of human endometrial cells in a three-dimensional culture system. J Reprod Fertil. 1994;101(2):327–332.

    Article  CAS  PubMed  Google Scholar 

  43. Bentin-Ley U, Sjogren A, Nilsson L, et al. Presence of uterine pinopodes at the embryo-endometrial interface during human implantation in vitro. Hum Reprod. 1999;14(2):515–520.

    Article  CAS  PubMed  Google Scholar 

  44. Bentin-Ley U, Horn T, Sjogren A, Sorensen S, Falck Larsen J, Hamberger L. Ultrastructure of human blastocyst-endometrial interactions in vitro. J Reprod Fertil. 2000;120(2):337–350.

    Article  CAS  PubMed  Google Scholar 

  45. Lopata A, tin-Ley U, Enders A. ‘‘Pinopodes’’ and implantation. Rev Endocr Metab Disord. 2002;3(2):77–86.

    Article  PubMed  Google Scholar 

  46. Petersen A, tin-Ley U, Ravn V, et al. The antiprogesterone Org 31710 inhibits human blastocyst-endometrial interactions in vitro. Fertil Steril. 2005;83(suppl 1):1255–1263.

    Article  CAS  PubMed  Google Scholar 

  47. Lalitkumar PG, Lalitkumar S, Meng CX, et al. Mifepristone, but not levonorgestrel, inhibits human blastocyst attachment to an in vitro endometrial three-dimensional cell culture model. Hum Reprod. 2007;22(11):3031–3037.

    Article  CAS  PubMed  Google Scholar 

  48. Meng CX, Andersson KL, tin-Ley U, Gemzell-Danielsson K, Lalitkumar PG. Effect of levonorgestrel and mifepristone on endometrial receptivity markers in a three-dimensional human endometrial cell culture model. Fertil Steril. 2009;91(1):256–264.

    Article  CAS  PubMed  Google Scholar 

  49. Classen-Linke I, Kusche M, Knauthe R, Beier HM. Establishment of a human endometrial cell culture system and characterization of its polarized hormone responsive epithelial cells. Cell Tissue Res. 1997;287(1):171–185.

    Article  CAS  PubMed  Google Scholar 

  50. Barmat LI, Liu HC, Spandorfer SD, et al. Autologous endometrial co-culture in patients with repeated failures of implantation after in vitro fertilization-embryo transfer. J. Assist. Reprod. Genet. 1999;16(3):121–127.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Rubio C, Simon C, Mercader A, Garcia-Velasco J, Remohí J, Pellicer A. Clinical experience employing co-culture of human embryos with autologous human endometrial epithelial cells. Hum Reprod. 2000;15(suppl 6):31–38.

    PubMed  Google Scholar 

  52. Spandorfer SD, Barmat LI, Navarro J, Liu HC, Veeck L, Rosenwaks Z. Importance of the biopsy date in autologous endometrial cocultures for patients with multiple implantation failures. Fertil Steril. 2002;77(6): 1209–1213.

    Article  PubMed  Google Scholar 

  53. Spandorfer SD, Barmat LI, Liu HC, Mele C, Veeck L, Rosenwaks Z. Granulocyte macrophage-colony stimulating factor production by autologous endometrial co-culture is associated with outcome for in vitro fertilization patients with a history of multiple implantation failures. Am J Reprod Immunol. 1998;40(5):377–381.

    Article  CAS  PubMed  Google Scholar 

  54. Nie G, Findlay JK, Salamonsen LA. Identification of novel endometrial targets for contraception. Contraception. 2005; 71(4):272–281.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Reproduction and Gynaecology, University Medical Center Utrecht, 3508 GA, PO Box 85500, Utrecht, Netherlands

    Gijs Teklenburg MD, MSc & Nick S. Macklon MD, PhD

Authors
  1. Gijs Teklenburg MD, MSc
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nick S. Macklon MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nick S. Macklon MD, PhD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Teklenburg, G., Macklon, N.S. In Vitro Models for the Study of Early Human Embryo-Endometrium Interactions. Reprod. Sci. 16, 811–818 (2009). https://doi.org/10.1177/1933719109334966

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1177/1933719109334966

Key words

Search

Navigation