Skip to main content

Advertisement

Log in

In Vitro Models to Study the Pathogenesis of Endometriosis

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

Abstract

Several in vitro models that attempt to replicate the intraperitoneal environment have been developed to study the pathogenesis of endometriosis. The chicken chorioallantotic membrane has been used, but it has not been well characterized and may introduce some species specific variables. In vitro models using human tissues include amniotic membrane, human peritoneal explants, and cell culture monolayers. These models have been used to qualitatively, quantitatively, and temporally assess attachment of endometrial cells to peritoneal mesothelial and subsequent transmesothelial invasion. These models have also been used to assess the role of cytokines in the development of the early endometriotic lesion. Two- and three dimensional invasion chamber models have been utilized to assess endometrial cell interactions with peritoneal mesothelial cells and the extracellular matrix. Invasion models are also useful to evaluate novel therapeutic approaches. This review will focus on the above models to assist reproductive scientists interested in the pathogenesis of endometriosis.

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

Access this article

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

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Sampson J. Peritoneal endometriosis due to the menstrual dissemination of endometrial tissue into the peritoneal cavity. Am J Obstet Gynecol. 1927;14:422–469.

    Article  Google Scholar 

  2. Halme J, Hammond MG, Hulka JF, Raj SG, Talbert LM. Retrograde menstruation in healthy women and in patients with endometriosis. Obstet Gynecol. 1984;64(2):151–154.

    CAS  PubMed  Google Scholar 

  3. Liu DT, Hitchcock A. Endometriosis: its association with retrograde menstruation, dysmenorrhoea and tubal pathology. Br J Obstet Gynaecol. 1986;93(8): 859–862.

    Article  CAS  Google Scholar 

  4. Keettel WC, Stein RJ. The viability of the cast-off menstrual endometrium. Am J Obstet Gynecol. 1951;61(2):440–442.

    Article  CAS  PubMed  Google Scholar 

  5. Mungyer G, Willemsen WN, Rolland R, et al. Cell of the mucous membrane of the female genital tract in culture: a comparative study with regard to the histogenesis of endometriosis. In Vitro Cell Dev Bio. 1987;23(2):111–117.

    Article  CAS  Google Scholar 

  6. Ridley JH, Edwards IK. Experimental endometriosis in the human. Am J Obstet Gynecol. 1958;76(4):783–790.

    Article  CAS  PubMed  Google Scholar 

  7. Olive DL, Henderson DY. Endometriosis and mullerian anomalies. Obstet Gynecol. 1987;69(3 pt 1):412–415.

    CAS  PubMed  Google Scholar 

  8. Sanfilippo JS, Wakim NG, Schikler KN, Yussman MA. Endometriosis in association with uterine anomaly. Am J Obstet Gynecol. 1986;154(1):39–43.

  9. Jenkins S, Olive DL, Haney AF. Endometriosis: pathogenetic implications of the anatomic distribution. Obstet Gynecol. 1986;67(3):335–338.

    CAS  PubMed  Google Scholar 

  10. Scher C, Haudenschild C, Klagsbrun M. The chick chorioallantoic membrane as a model system for the study of tissue invasion by viral transformed cells. Cell. 1976;8(3):373–382.

    Article  CAS  PubMed  Google Scholar 

  11. Armstrong PB, Quigley JP, Sidebottom E. Transepithelial invasion and intramesenchymal infiltration of the chick embryo chorioallantois by tumor cell lines. Cancer Res. 1982;42(5):1826–1837.

    CAS  PubMed  Google Scholar 

  12. Maas JW, Groothuis PG, Dunselman GA, de Goeij AF, Struijker-Boudier HA, Evers JL. Development of endometriosis-like lesions after transplantation of human endometrial fragments onto the chick embryo chorioallantoic membrane. Hum Reprod. 2001;16(4):627–631.

    Article  CAS  PubMed  Google Scholar 

  13. Nap AW, Groothuis PG, Demir AY, et al. Tissue integrity is essential for ectopic implantation of human endometrium in the chicken chorioallantoic membrane. Hum Reprod. 2003;18(1):30–34.

    Article  CAS  PubMed  Google Scholar 

  14. Giannopoulou E, Katsoris P, Hatziapostolou M, et al. X-rays modulate extracellular matrix in vivo. Int J Cancer. 2001;94(5):690–698.

    Article  CAS  PubMed  Google Scholar 

  15. Nap AW, Dunselman GA, Griffioen AW, Mayo KH, Evers JL, Groothuis PG. Angiostatic agents prevent the development of endometriosis-like lesions in the chicken chorioallantoic membrane. Fertil Steril. 2005;83(3):793–795.

    Article  PubMed  Google Scholar 

  16. Oosterlynck DJ, Meuleman C, Waer M, Koninckx PR, Vandeputte M. Immunosuppressive activity of peritoneal fluid in women with endometriosis. Obstet Gynecol. 1993;82(2):206–212.

    CAS  PubMed  Google Scholar 

  17. Liotta LA, Lee CW, Morakis DJ. New method for preparing large surfaces of intact human basement membrane for tumor invasion studies. Cancer Lett. 1980;11(2):141–152.

    Article  CAS  PubMed  Google Scholar 

  18. van der Linden PJ, de Goeij AF, Dunselman GA, Erkens HW, Evers JL. Endometrial cell adhesion in an in vitro model using intact amniotic membranes. Fertil Steril. 1996;65(1): 76–80.

    Article  PubMed  Google Scholar 

  19. La Rocca P, Rheinwald J. Coexpression of simple epithelia keratin and vimentin by human mesothelium and meso-thelioma in vivo and in culture. Cancer Res. 1984;44(7): 2991–2995.

    Google Scholar 

  20. Wild RA, Zhang RJ, Medders D. Whole endometrial fragments form characteristics of in vivo endometriosis in a mesothelial cell co-culture system: an in vitro model for the study of the histogenesis of endometriosis. J Soc Gynecol Investig. 1994;1(1):65–68.

    Article  CAS  PubMed  Google Scholar 

  21. Witz CA, Montoya-Rodriguez IA, Miller DM, Schneider BG, Schenken RS. Mesothelium expression of integrins in vivo and in vitro. J Soc Gynecol Invest. 1998;5(2): 87–93.

    Article  CAS  Google Scholar 

  22. van der Linden PJ, de Goeij AF, Dunselman GA, Erkens HW, Evers JL. Amniotic membrane as an in vitro model for endometrium-extracellular matrix interactions. Gynecol Obstet Invest. 1998;45(1):7–11.

    Article  PubMed  Google Scholar 

  23. Witz CA, Montoya IA, Schenken RS. Whole explants of peritoneum and endometrium: a novel model of the early endometriosis lesion. Fertil Steril. 1999;71(1):56–60.

    Article  CAS  PubMed  Google Scholar 

  24. Groothuis P, Koks CA, de Goeij AF, Dunselman GA, Arends JW, Evers JL. Adhesion of human endometrial fragments to peritoneum in vitro. Fertil Steril. 1999;71(6):1119–1124.

    Article  CAS  PubMed  Google Scholar 

  25. Koks CA, Groothuis PG, Dunselman GA, de Goeij AF, Evers JL. Adhesion of shed menstrual tissue in an in-vitro model using amnion and peritoneum: a light and electron microscopic study. Hum Reprod. 1999;14(3):816–822.

    Article  CAS  PubMed  Google Scholar 

  26. Witz CA, Thomas MR, Montoya-Rodriguez IA, Nair AS, Centonze VE, Schenken RS. Short-term culture of peritoneum explants confirms attachment of endometrium to intact peritoneal mesothelium. Fertil Stertil. 2001;75(2):385–390.

    Article  CAS  Google Scholar 

  27. Witz CA, Cho S, Centonze VE, Montoya-Rodriguez IA, Schenken RS. Time series analysis of transmesothelial invasion by endometrial stromal and epithelial cells using three-dimensional confocal microscopy. Fertil Steril. 2003;79(suppl 1):770–778.

    Article  PubMed  Google Scholar 

  28. Witz CA, Allsup KT, Montoya-Rodriguez IA, Vaughn SL, Centonze VE, Schenken RS. Culture of menstrual endometrium with peritoneal explants and mesothelial monolayers confirms attachment to intact mesothelial cells. Hum Reprod. 2002;17(11):2832–2838.

    Article  PubMed  Google Scholar 

  29. Lucidi RS, Witz CA, Chrisco M, Binkley PA, Shain SA, Schenken RS. A novel in vitro model of the early endometriotic lesion demonstrates that attachment of endometrial cells to mesothelial cells is dependent on the source of endometrial cells. Fertil Steril. 2005;84(1):16–21.

    Article  PubMed  Google Scholar 

  30. Griffith J, Lui YG, Binkley PA, Tekmal RR, Holden AEC, Schenken RS. Menstrual endometrial cells from women with endometriosis demonstrate increased adherence to peritoneal cells and increased expression of CD44 splice variants. Fertil Steril. IN PRESS.

  31. Naor D, Sionov RV, Ish-Shalom D. CD44: structure, function and association with the malignant process. Adv Cancer Res. 1997;71:241–319.

    Article  CAS  PubMed  Google Scholar 

  32. Aruffo A, Stamenkovic I, Melnick M, Underhill CB, Seed B. CD44 is the principal cell surface receptor for hyaluronate. Cell. 1990;61(7):1303–1313.

    Article  CAS  PubMed  Google Scholar 

  33. Heldin P, Pertoff H. Synthesis and assembly of the hyaluronan-coating coats around normal human mesothelial cells. Exp Cell Res. 1993;208(2):422–429.

    Article  CAS  PubMed  Google Scholar 

  34. Cannistra SA, Kansas GS, Niloff J, DeFranzo B, Kim Y, Ottensmeier C. Binding of ovarian cancer cells to peritoneal mesothelium in vitro is partly mediated by CD44H. Cancer Res. 1993;53(16):3830–3838.

    CAS  PubMed  Google Scholar 

  35. Lessan K, Aguiar DJ, Oegema T, Siebenson L, Skubitz AP. CD44 and beta 1 integrin mediate ovarian carcinoma cell adhesion to peritoneal mesothelial cells. Am J Pathol. 1999;154(5):1525–1537.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Witz CA, Takahashi A, Montoya-Rodriguez IA, Cho S, Schenken RS. Expression of the a2B1 and a3B1 integrins at the surface of mesothelial cells: a potential attachment site of endometrial cells. Fertil Steril. 2000;74(3):579–584.

    Article  CAS  PubMed  Google Scholar 

  37. Tietze L, Borntraeger J, Klosterhalfen B, et al. Expression and function of beta(1) and beta(3) integrins of human mesothelial cells in vitro. Exp Mol Pathol. 1999;66(2):131–139.

    Article  CAS  PubMed  Google Scholar 

  38. Witz CA, Cho S, Montoya-Rodriguez IA, Schenken RS. The alpha(2)beta(1) and alpha(3)beta(1) integrins do not mediate attachment of endometrial cells to peritoneal mesothelium. Fertil Steril. 2002;78(4):796–803.

    Article  PubMed  Google Scholar 

  39. Witz CA, Montoya-Rodriguez IA, Cho S, Centonze VE, Bonewald LE, Schenken RS. Composition of the extraceullar matrix of the peritoneum. J Soc Gynecol Invest. 2001;8(5): 299–304.

    Article  CAS  Google Scholar 

  40. Oral E, Olive DL, Arici A. The peritoneal environment in endometriosis. Hum Reprod Update. 1996;2(5):385–398.

    Article  CAS  PubMed  Google Scholar 

  41. Zhang RJ, Wild RA, Ojago JM. Effect of tumor necrosis factor-alpha on adhesion of human endometrial stromal cells to peritoneal mesothelial cells: an in vitro system. Fertil Steril. 1993;59(6):1196–1201.

    Article  CAS  PubMed  Google Scholar 

  42. Debrock S, De Strooper B, Vander Perre S, Hill JA, D’Hooghe TM. Tumour necrosis factor-alpha, interleukin-6 and interleukin-8 do not promote adhesion of human endometrial epithelial cells to mesothelial cells in a quantitative in vitro model. Hum Reprod. 2006;21(3):605–609.

    Article  CAS  PubMed  Google Scholar 

  43. Sillem M, Prifti S, Monga B, Arslic T, Runnebaum B. Integrin-mediated adhesion of uterine endometrial cells from endometriosis patients to extracellular matrix proteins is enhanced by tumor necrosis factor alpha (TNF alpha) and interleukin-1 (IL-1). Eur J Obstet Gynecol Reprod Biol. 1999; 87(2):123–127.

    Article  CAS  PubMed  Google Scholar 

  44. Iwabe T, Harada T, Tsudo T, et al. Tumor necrosis factor-alpha promotes proliferation of endometriotic stromal cells by inducing interleukin-8 gene and protein expression. J Clin Endocrinol Metab. 2000;85(2):824–829.

    CAS  PubMed  Google Scholar 

  45. Braun DP, Ding J, Dmowski WP. Peritoneal fluid-mediated enhancement of eutopic and ectopic endometrial cell proliferation is dependent on tumor necrosis factor-alpha in women with endometriosis. Fertil Steril. 2002;78(4):727–732.

    Article  PubMed  Google Scholar 

  46. Bouhadir KH, Mooney DJ. In vitro and in vivo models for the reconstruction of intercellular signaling. Ann N Y Acad Sci. 1998;842:188–194.

    Article  CAS  PubMed  Google Scholar 

  47. O’Brien LE, Zegers MM, Mostov KE. Opinion: building epithelial architecture: insights from three-dimensional culture models. Nat Rev Mol Cell Biol. 2002;3(7):531–537.

    Article  CAS  PubMed  Google Scholar 

  48. Santini MT, Rainaldi G, Indovina PL. Apoptosis, cell adhesion and the extracellular matrix in the three-dimensional growth of multicellular tumor spheroids. Crit Rev Oncol Hematol. 2000;36(2–3):75–87.

    Article  CAS  PubMed  Google Scholar 

  49. Kleinman HK, McGarvey ML, Liotta LA, Robey PG, Tryggvason K, Martin GR. Isolation and characterization of type IV procollagen, laminin, and heparan sulfate proteoglycan from the EHS sarcoma. Biochemistry. 1982;21(24):6188–6193.

    Article  CAS  PubMed  Google Scholar 

  50. Kleinman HK, McGarvey ML, Hassell JR, et al. Basement membrane complexes with biological activity. Biochemistry. 1986;25(2):312–318.

    Article  CAS  PubMed  Google Scholar 

  51. Kobayashi H. Invasive capacity of heterotopic endometrium. Gynecol Obstet Invest. 2000;50(suppl 1):26–32.

    Article  PubMed  Google Scholar 

  52. Zeitvogel A, Baumann R, Starzinski-Powitz A. Identification of an invasive, N-cadherin-expressing epithelial cell type in endometriosis using a new cell culture model. Am J Pathol. 2001;159(5):1839–1852.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Nair AS, Nair HB, Lucidi RS, et al. Modeling the early endometriotic lesion: mesothelium-endometrial cell co-culture increases endometrial invasion and alters mesothelial and endometrial gene transcription. Fertil Steril. 2008;90(4 suppl):1487–1495.

    Article  PubMed  Google Scholar 

  54. Fasciani A, Bocci G, Xu J, et al. Three-dimensional in vitro culture of endometrial explants mimics the early stages of endometriosis. Fertil Steril. 2003;80(5):1137–1143.

    Article  PubMed  Google Scholar 

  55. Esfandiari N, Khazaei M, Ai J, et al. Effect of a statin on an in vitro model of endometriosis. Fertil Steril. 2007;87(2): 257–262.

    Article  CAS  PubMed  Google Scholar 

  56. Bittinger F, Brochhausen C, Skarke C, Kohler H, Kirkpatrick CJ. Reconstruction of peritoneal-like structure in three-dimensional collagen gel matrix culture. Exp Cell Res. 1997;236(1):155–160.

    Article  CAS  PubMed  Google Scholar 

  57. Yang H, Han S, Kim H, et al. Expression of integrins, cyclooxygenases and matrix metalloproteinases in three-dimensional human endometrial cell culture system. Exp Mol Med. 2002;34(1):75–82.

    Article  CAS  PubMed  Google Scholar 

  58. Griffith JS, Binkley PA, Kirma NB, Schenken RS, Tekmal RR, Witz CA. Imatinib decreases endometrial stromal cell transmesothelial migration and proliferation in the extracellular matrix of modeled peritoneum. Fertil Steril. 2007;88(suppl 1):S60–S61.

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Robert S. Schenken MD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Griffith, J.S., Rodgers, A.K. & Schenken, R.S. In Vitro Models to Study the Pathogenesis of Endometriosis. Reprod. Sci. 17, 5–12 (2010). https://doi.org/10.1177/1933719109338221

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1177/1933719109338221

Key words

Navigation