Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Strategies for modelling endometrial diseases

Abstract

Each month during a woman’s reproductive years, the endometrium undergoes vast changes to prepare for a potential pregnancy. Diseases of the endometrium arise for numerous reasons, many of which remain unknown. These endometrial diseases, including endometriosis, adenomyosis, endometrial cancer and Asherman syndrome, affect many women, with an overall lack of efficient or permanent treatment solutions. The challenge lies in understanding the complexity of the endometrium and the extensive changes, orchestrated by ovarian hormones, that occur in multiple cell types over the period of the menstrual cycle. Appropriate model systems that closely mimic the architecture and function of the endometrium and its diseases are needed. The emergence of organoid technology using human cells is enabling a revolution in modelling the endometrium in vitro. The goal of this Review is to provide a focused reference for new models to study the diseases of the endometrium. We provide perspectives on the power of new and emerging models, from organoids to microfluidics, which have opened up a new frontier for studying endometrial diseases.

Key points

  • Endometrial diseases, including Asherman syndrome, endometriosis, adenomyosis and endometrial cancer, represent a major health burden in reproductive-age women and do not have effective therapies.

  • Traditional in vitro culture techniques have long been used to study endometrial diseases, but they are limited by using single cell types and static cultures.

  • Emerging technologies, such as organoids and microphysiological systems, are physiologically relevant and can reproduce many characteristics of native tissues and disease states.

  • Although multiple microphysiological systems that model the endometrium have been developed, most of these have not yet been applied to endometrial diseases.

  • Further innovations in organoid and microfluidic models will enable more accurate endometrial disease modelling and drug testing.

This is a preview of subscription content, access via your institution

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: The human endometrium and its most common pathologies.
Fig. 2: In vitro models of endometrial diseases.
Fig. 3: Current approaches to model the endometrial niche and pathologies using microfluidic technologies.
Fig. 4: Idealized design of MPS of the healthy endometrium and its diseases.

References

  1. Critchley, H. O. D., Maybin, J. A., Armstrong, G. M. & Williams, A. R. W. Physiology of the endometrium and regulation of menstruation. Physiol. Rev. 100, 1149–1179 (2020).

    Article  PubMed  Google Scholar 

  2. Salamonsen, L. A., Hutchison, J. C. & Gargett, C. E. Cyclical endometrial repair and regeneration. Development 148, dev199577 (2021).

    Article  CAS  PubMed  Google Scholar 

  3. Jain, V., Chodankar, R. R., Maybin, J. A. & Critchley, H. O. D. Uterine bleeding: how understanding endometrial physiology underpins menstrual health. Nat. Rev. Endocrinol. 18, 290–308 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Conforti, A., Alviggi, C., Mollo, A., De Placido, G. & Magos, A. The management of Asherman syndrome: a review of literature. Reprod. Biol. Endocrinol. 11, 118 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Dreisler, E. & Kjer, J. J. Asherman’s syndrome: current perspectives on diagnosis and management. Int. J. Women’s Health 11, 191–198 (2019).

    Article  Google Scholar 

  6. Chapron, C. et al. Diagnosing adenomyosis: an integrated clinical and imaging approach. Hum. Reprod. Update 26, 392–411 (2020).

    Article  PubMed  Google Scholar 

  7. Habiba, M., Gordts, S., Bazot, M., Brosens, I. & Benagiano, G. Exploring the challenges for a new classification of adenomyosis. Reprod. Biomed. Online 40, 569–581 (2020).

    Article  PubMed  Google Scholar 

  8. Bulun, S. E. Endometriosis. N. Engl. J. Med. 360, 268–279 (2009).

    Article  CAS  PubMed  Google Scholar 

  9. Kim, J. J. & Chapman-Davis, E. Role of progesterone in endometrial cancer. Semin. Reprod. Med. 28, 81–90 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Fitzgerald, H. C., Schust, D. J. & Spencer, T. E. In vitro models of the human endometrium: evolution and application for women’s health. Biol. Reprod. 104, 282–293 (2021).

    Article  PubMed  Google Scholar 

  11. Heremans, R., Jan, Z., Timmerman, D. & Vankelecom, H. Organoids of the female reproductive tract: innovative tools to study desired to unwelcome processes. Front. Cell Dev. Biol. 9, 661472 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Song, Y. & Fazleabas, A. T. Endometrial organoids: a rising star for research on endometrial development and associated diseases. Reprod. Sci. 28, 1626–1636 (2021).

    Article  PubMed  Google Scholar 

  13. Campo, H. et al. Microphysiological modeling of the human endometrium. Tissue Eng. Part A 26, 759–768 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Cadena, I., Chen, A., Arvidson, A. & Fogg, K. C. Biomaterial strategies to replicate gynecological tissue. Biomater. Sci. 9, 1117–1134 (2021).

    Article  CAS  PubMed  Google Scholar 

  15. Mancini, V. & Pensabene, V. Organs-on-chip models of the female reproductive system. Bioengineering 6, 103 (2019).

    Article  CAS  PubMed Central  Google Scholar 

  16. Young, R. E. & Huh, D. D. Organ-on-a-chip technology for the study of the female reproductive system. Adv. Drug Deliv. Rev. 173, 461–478 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kelleher, A. M., DeMayo, F. J. & Spencer, T. E. Uterine glands: developmental biology and functional roles in pregnancy. Endocr. Rev. 40, 1424–1445 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Cooke, P. S., Spencer, T. E., Bartol, F. F. & Hayashi, K. Uterine glands: development, function and experimental model systems. Mol. Hum. Reprod. 19, 547–558 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Gray, C. A. et al. Developmental biology of uterine glands. Biol. Reprod. 65, 1311–1323 (2001).

    Article  CAS  PubMed  Google Scholar 

  20. Garcia-Alonso, L. et al. Mapping the temporal and spatial dynamics of the human endometrium in vivo and in vitro. Nat. Genet. 53, 1698–1711 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Wang, W. et al. Single-cell transcriptomic atlas of the human endometrium during the menstrual cycle. Nat. Med. 26, 1644–1653 (2020).

    Article  CAS  PubMed  Google Scholar 

  22. Yamaguchi, M. et al. Spatiotemporal dynamics of clonal selection and diversification in normal endometrial epithelium. Nat. Commun. 13, 943 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Yamaguchi, M. et al. Three-dimensional understanding of the morphological complexity of the human uterine endometrium. iScience 24, 102258 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Krikun, G., Mor, G. & Lockwood, C. The immortalization of human endometrial cells. Methods Mol. Med. 121, 79–83 (2006).

    PubMed  Google Scholar 

  25. Kyo, S. et al. Successful immortalization of endometrial glandular cells with normal structural and functional characteristics. Am. J. Pathol. 163, 2259–2269 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Park, Y. et al. A novel human endometrial epithelial cell line for modeling gynecological diseases and for drug screening. Lab. Invest. 101, 1505–1512 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Yuhki, M., Kajitani, T., Mizuno, T., Aoki, Y. & Maruyama, T. Establishment of an immortalized human endometrial stromal cell line with functional responses to ovarian stimuli. Reprod. Biol. Endocrinol. 9, 104 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Bongso, A. et al. Establishment of human endometrial cell cultures. Hum. Reprod. 3, 705–713 (1988).

    Article  CAS  PubMed  Google Scholar 

  29. Michalski, S. A., Chadchan, S. B., Jungheim, E. S. & Kommagani, R. Isolation of human endometrial stromal cells for in vitro decidualization. J. Vis. Exp. 139, e57684 (2018).

    Google Scholar 

  30. Gellersen, B., Brosens, I. A. & Brosens, J. J. Decidualization of the human endometrium: mechanisms, functions, and clinical perspectives. Semin. Reprod. Med. 25, 445–453 (2007).

    Article  CAS  PubMed  Google Scholar 

  31. Gellersen, B. & Brosens, J. Cyclic AMP and progesterone receptor cross-talk in human endometrium: a decidualizing affair. J. Endocrinol. 178, 357–372 (2003).

    Article  CAS  PubMed  Google Scholar 

  32. Gellersen, B. & Brosens, J. J. Cyclic decidualization of the human endometrium in reproductive health and failure. Endocr. Rev. 35, 851–905 (2014).

    Article  CAS  PubMed  Google Scholar 

  33. Cloke, B. et al. The androgen and progesterone receptors regulate distinct gene networks and cellular functions in decidualizing endometrium. Endocrinology 149, 4462–4474 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Schindler, A. E. et al. Classification and pharmacology of progestins. Maturitas 61, 171–180 (2008).

    Article  PubMed  Google Scholar 

  35. Kim, J. J., Jaffe, R. C. & Fazleabas, A. T. Comparative studies on the in vitro decidualization process in the baboon (Papio anubis) and human. Biol. Reprod. 59, 160–168 (1998).

    Article  CAS  PubMed  Google Scholar 

  36. Kim, J. J. et al. Regulation of insulin-like growth factor binding protein-1 promoter activity by FKHR and HOXA10 in primate endometrial cells. Biol. Reprod. 68, 24–30 (2003).

    Article  CAS  PubMed  Google Scholar 

  37. Schäfer, W. R. et al. Critical evaluation of human endometrial explants as an ex vivo model system: a molecular approach. Mol. Hum. Reprod. 17, 255–265 (2011).

    Article  PubMed  Google Scholar 

  38. Blauer, M., Heinonen, P. K., Martikainen, P. M., 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. 20, 864–871 (2005).

    Article  CAS  PubMed  Google Scholar 

  39. Schutte, S. C., James, C. O., Sidell, N. & Taylor, R. N. Tissue-engineered endometrial model for the study of cell–cell interactions. Reprod. Sci. 22, 308–315 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Zambuto, S. G., Clancy, K. B. H. & Harley, B. A. C. A gelatin hydrogel to study endometrial angiogenesis and trophoblast invasion. Interface Focus. 9, 20190016 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Li, S. & Ding, L. Endometrial perivascular progenitor cells and uterus regeneration. J. Pers. Med. 11, 477 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Sweeney, M. & Foldes, G. It takes two: endothelial-perivascular cell cross-talk in vascular development and disease. Front. Cardiovasc. Med. 5, 154 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Zhu, X. et al. Human endometrial perivascular stem cells exhibit a limited potential to regenerate endometrium after xenotransplantation. Hum. Reprod. 36, 145–159 (2021).

    CAS  PubMed  Google Scholar 

  44. Turco, M. Y. et al. Long-term, hormone-responsive organoid cultures of human endometrium in a chemically defined medium. Nat. Cell Biol. 19, 568–577 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Boretto, M. et al. Development of organoids from mouse and human endometrium showing endometrial epithelium physiology and long-term expandability. Development 144, 1775–1786 (2017).

    CAS  PubMed  Google Scholar 

  46. Fitzgerald, H. C., Dhakal, P., Behura, S. K., Schust, D. J. & Spencer, T. E. Self-renewing endometrial epithelial organoids of the human uterus. Proc. Natl Acad. Sci. USA 116, 23132–23142 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Wiwatpanit, T. et al. Scaffold-free endometrial organoids respond to excess androgens associated with polycystic ovarian syndrome. J. Clin. Endocrinol. Metab. 105, 769–780 (2020).

    Article  Google Scholar 

  48. Rawlings, T. M. et al. Modelling the impact of decidual senescence on embryo implantation in human endometrial assembloids. eLife 10, e69603 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Cindrova-Davies, T. et al. Menstrual flow as a non-invasive source of endometrial organoids. Commun. Biol. 4, 651 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Filby, C. E. et al. Comparison of organoids from menstrual fluid and hormone-treated endometrium: novel tools for gynecological research. J. Pers. Med. 11, 1314 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Alzamil, L., Nikolakopoulou, K. & Turco, M. Y. Organoid systems to study the human female reproductive tract and pregnancy. Cell Death Differ. 28, 35–51 (2021).

    Article  PubMed  Google Scholar 

  52. Watson, D. E., Hunziker, R. & Wikswo, J. P. Fitting tissue chips and microphysiological systems into the grand scheme of medicine, biology, pharmacology, and toxicology. Exp. Biol. Med. 242, 1559–1572 (2017).

    Article  CAS  Google Scholar 

  53. Marx, U. et al. Biology-inspired microphysiological systems to advance patient benefit and animal welfare in drug development. ALTEX 37, 365–394 (2020).

    PubMed  PubMed Central  Google Scholar 

  54. Regehr, K. J. et al. Biological implications of polydimethylsiloxane-based microfluidic cell culture. Lab Chip 9, 2132–2139 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Sung, J. H. et al. Recent advances in body-on-a-chip systems. Anal. Chem. 91, 330–351 (2019).

    Article  CAS  PubMed  Google Scholar 

  56. Edington, C. D. et al. Interconnected microphysiological systems for quantitative biology and pharmacology studies. Sci. Rep. 8, 4530 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Theobald, J. et al. Liver-kidney-on-chip to study toxicity of drug metabolites. ACS Biomater. Sci. Eng. 4, 78–89 (2018).

    Article  CAS  PubMed  Google Scholar 

  58. Shinha, K. et al. A kinetic pump integrated microfluidic plate (KIM-Plate) with high usability for cell culture-based multiorgan microphysiological systems. Micromachines 12, 1007 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Rogers, H. B. et al. Dental resins used in 3D printing technologies release ovo-toxic leachates. Chemosphere 270, 129003 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Gnecco, J. S. et al. Compartmentalized culture of perivascular stroma and endothelial cells in a microfluidic model of the human endometrium. Ann. Biomed. Eng. 45, 1758–1769 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  61. Gnecco, J. S. et al. Hemodynamic forces enhance decidualization via endothelial-derived prostaglandin E2 and prostacyclin in a microfluidic model of the human endometrium. Hum. Reprod. 34, 702–714 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Ahn, J. et al. Three-dimensional microengineered vascularised endometrium-on-a-chip. Hum. Reprod. 36, 2720–2731 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. De Bem, T. H. C., Tinning, H., Vasconcelos, E. J. R., Wang, D. & Forde, N. Endometrium on-a-chip reveals insulin- and glucose-induced alterations in the transcriptome and proteomic secretome. Endocrinology 162, bqab054 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Xiao, S. et al. A microfluidic culture model of the human reproductive tract and 28-day menstrual cycle. Nat. Commun. 8, 14584 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Park, S. R. et al. Development of a novel dual reproductive organ on a chip: recapitulating bidirectional endocrine crosstalk between the uterine endometrium and the ovary. Biofabrication 13, 015001 (2021).

    Article  CAS  Google Scholar 

  66. Yu, D., Wong, Y. M., Cheong, Y., Xia, E. & Li, T. C. Asherman syndrome–one century later. Fertil. Steril. 89, 759–779 (2008).

    Article  PubMed  Google Scholar 

  67. Foix, A., Bruno, R. O., Davison, T. & Lema, B. The pathology of postcurettage intrauterine adhesions. Am. J. Obstet. Gynecol. 96, 1027–1033 (1966).

    Article  CAS  PubMed  Google Scholar 

  68. Schenker, J. G. & Margalioth, E. J. Intrauterine adhesions: an updated appraisal. Fertil. Steril. 37, 593–610 (1982).

    Article  CAS  PubMed  Google Scholar 

  69. Asherman, J. G. Amenorrhoea traumatica (atretica). J. Obstet. Gynaecol. Br. Emp. 55, 23–30 (1948).

    Article  CAS  PubMed  Google Scholar 

  70. Wang, J. et al. Application of bone marrow-derived mesenchymal stem cells in the treatment of intrauterine adhesions in rats. Cell Physiol. Biochem. 39, 1553–1560 (2016).

    Article  CAS  PubMed  Google Scholar 

  71. Gargett, C. E. & Healy, D. L. Generating receptive endometrium in Asherman’s syndrome. J. Hum. Reprod. Sci. 4, 49–52 (2011).

    PubMed  PubMed Central  Google Scholar 

  72. Cervello, I. et al. Human CD133+ bone marrow-derived stem cells promote endometrial proliferation in a murine model of Asherman syndrome. Fertil. Steril. 104, 1552–1560.e1–3 (2015).

    Article  PubMed  Google Scholar 

  73. Zhang, S., Li, P., Yuan, Z. & Tan, J. Platelet-rich plasma improves therapeutic effects of menstrual blood-derived stromal cells in rat model of intrauterine adhesion. Stem Cell Res. Ther. 10, 61 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Xu, L. et al. Umbilical cord-derived mesenchymal stem cells on scaffolds facilitate collagen degradation via upregulation of MMP-9 in rat uterine scars. Stem Cell Res. Ther. 8, 84 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Jing, Z., Qiong, Z., Yonggang, W. & Yanping, L. Rat bone marrow mesenchymal stem cells improve regeneration of thin endometrium in rat. Fertil. Steril. 101, 587–594 (2014).

    Article  CAS  PubMed  Google Scholar 

  76. Domnina, A. et al. Human mesenchymal stem cells in spheroids improve fertility in model animals with damaged endometrium. Stem Cell Res. Ther. 9, 50 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Jiang, X. et al. Endometrial membrane organoids from human embryonic stem cell combined with the 3D Matrigel for endometrium regeneration in asherman syndrome. Bioact. Mater. 6, 3935–3946 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. de Miguel-Gomez, L. et al. Comparison of different sources of platelet-rich plasma as treatment option for infertility-causing endometrial pathologies. Fertil. Steril. 115, 490–500 (2021).

    Article  PubMed  Google Scholar 

  79. Liu, F. et al. Hyaluronic acid hydrogel integrated with mesenchymal stem cell-secretome to treat endometrial injury in a rat model of Asherman’s syndrome. Adv. Healthc. Mater. 8, e1900411 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  80. Giudice, L. C. & Kao, L. C. Endometriosis. Lancet 364, 1789–1799 (2004).

    Article  PubMed  Google Scholar 

  81. Sampson, J. A. Metastatic or embolic endometriosis, due to the menstrual dissemination of endometrial tissue into the venous circulation. Am. J. Pathol. 3, 93–110.43 (1927).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Bulun, S. E. et al. Progesterone resistance in endometriosis: link to failure to metabolize estradiol. Mol. Cell Endocrinol. 248, 94–103 (2006).

    Article  CAS  PubMed  Google Scholar 

  83. Bulun, S. E. et al. Endometriosis. Endocr. Rev. 40, 1048–1079 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  84. Yin, P. et al. Progesterone receptor regulates Bcl-2 gene expression through direct binding to its promoter region in uterine leiomyoma cells. J. Clin. Endocrinol. Metab. 92, 4459–4466 (2007).

    Article  CAS  PubMed  Google Scholar 

  85. Yin, X., Pavone, M. E., Lu, Z., Wei, J. & Kim, J. J. Increased activation of the PI3K/AKT pathway compromises decidualization of stromal cells from endometriosis. J. Clin. Endocrinol. Metab. 97, E35–E43 (2012).

    Article  CAS  PubMed  Google Scholar 

  86. Hey-Cunningham, A. J. et al. Angiogenesis, lymphangiogenesis and neurogenesis in endometriosis. Front. Biosci. 5, 1033–1056 (2013).

    Article  Google Scholar 

  87. D’Hooghe, T. M., Bambra, C. S., Cornillie, F. J., Isahakia, M. & Koninckx, P. R. Prevalence and laparoscopic appearance of spontaneous endometriosis in the baboon (Papio anubis, Papio cynocephalus). Biol. Reprod. 45, 411–416 (1991).

    Article  PubMed  Google Scholar 

  88. MacKenzie, W. F. & Casey, H. W. Animal model of human disease. Endometriosis. Animal model: endometriosis in rhesus monkeys. Am. J. Pathol. 80, 341–344 (1975).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Gu, Z. Y., Jia, S. Z. & Leng, J. H. Establishment of endometriotic models: the past and future. Chin. Med. J. 133, 1703–1710 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  90. Sulaiman, H., Dawson, L., Laurent, G. J., Bellingan, G. J. & Herrick, S. E. Role of plasminogen activators in peritoneal adhesion formation. Biochem. Soc. Trans. 30, 126–131 (2002).

    Article  CAS  PubMed  Google Scholar 

  91. Fasciani, A. et al. Three-dimensional in vitro culture of endometrial explants mimics the early stages of endometriosis. Fertil. Steril. 80, 1137–1143 (2003).

    Article  PubMed  Google Scholar 

  92. Esfandiari, N. et al. Expression of glycodelin and cyclooxygenase-2 in human endometrial tissue following three-dimensional culture. Am. J. Reprod. Immunol. 57, 49–54 (2007).

    Article  CAS  PubMed  Google Scholar 

  93. Esfandiari, N. et al. Effect of a statin on an in vitro model of endometriosis. Fertil. Steril. 87, 257–262 (2007).

    Article  CAS  PubMed  Google Scholar 

  94. Prechapanich, J. et al. Effect of a dienogest for an experimental three-dimensional endometrial culture model for endometriosis. Med. Mol. Morphol. 47, 189–195 (2013).

    Article  PubMed  Google Scholar 

  95. Esfandiari, N., Nazemian, Z. & Casper, R. F. Three-dimensional culture of endometrial cells: an in vitro model of endometriosis. Am. J. Reprod. Immunol. 60, 283–289 (2008).

    Article  PubMed  Google Scholar 

  96. Maas, J. W. M. et al. The chick embryo chorioallantoic membrane as a model to investigate the angiogenic properties of human endometrium. Gynecol. Obstet. Invest. 48, 108–112 (1999).

    Article  CAS  PubMed  Google Scholar 

  97. Nap, A. W. et al. Angiostatic agents prevent the development of endometriosis-like lesions in the chicken chorioallantoic membrane. Fertil. Steril. 83, 793–795 (2005).

    Article  PubMed  Google Scholar 

  98. Nap, A. W. et al. Oral contraceptives prevent the development of endometriosis in the chicken chorioallantoic membrane model. Contraception 78, 257–265 (2008).

    Article  CAS  PubMed  Google Scholar 

  99. Groothuis, P. G. et al. Adhesion of human endometrial fragments to peritoneum in vitro. Fertil. Steril. 71, 1119–1124 (1999).

    Article  CAS  PubMed  Google Scholar 

  100. Koks, C. A. M., Groothuis, P. G., Dunselman, G. A. J., Goeij, A. F. P. M. D. & Evers, J. L. H. Adhesion of shed menstrual tissue in an in-vitro model using amnion and peritoneum: a light and electron microscopic study. Hum. Reprod. 14, 816–822 (1999).

    Article  CAS  PubMed  Google Scholar 

  101. Witz, C. A., Monotoya-Rodriguez, I. A. & Schenken, R. S. Whole explants of peritoneum and endometrium: a novel model of the early endometriosis lesion. Fertil. Steril. 71, 56–60 (1999).

    Article  CAS  PubMed  Google Scholar 

  102. van der Linden, P. J. Q., Goeij, A. F. P. Md, Dunselman, G. A. J., Erkens, H. W. H. & Evers, J. L. H. Amniotic membrane as an in vitro model for endometrium–extracellular matrix interactions. Gynecol. Obstet. Invest. 45, 7–11 (1998).

    Article  PubMed  Google Scholar 

  103. Lee, Y. J. & Yi, K. W. Bone marrow-derived stem cells contribute to regeneration of the endometrium. Clin. Exp. Reprod. Med. 45, 149–153 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Chen, P., Mamillapalli, R., Habata, S. & Taylor, H. S. Endometriosis cell proliferation induced by bone marrow mesenchymal stem cells. Reprod. Sci. 28, 426–434 (2020).

    Article  PubMed  Google Scholar 

  105. Zhang, W. et al. 17β-estradiol promotes bone marrow mesenchymal stem cell migration mediated by chemokine upregulation. Biochem. Biophys. Res. Commun. 530, 381–388 (2020).

    Article  CAS  PubMed  Google Scholar 

  106. de Miguel-Gomez, L. et al. Stem cells and the endometrium: from the discovery of adult stem cells to pre-clinical models. Cells 10, 595 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  107. Kucia, M. et al. Bone marrow as a home of heterogenous populations of nonhematopoietic stem cells. Leukemia 19, 1118–1127 (2005).

    Article  CAS  PubMed  Google Scholar 

  108. Symons, L. K. et al. The immunopathophysiology of endometriosis. Trends Mol. Med. 24, 748–762 (2018).

    Article  CAS  PubMed  Google Scholar 

  109. Mei, J., Chang, K. K. & Sun, H. X. Immunosuppressive macrophages induced by IDO1 promote the growth of endometrial stromal cells in endometriosis. Mol. Med. Rep. 15, 2255–2260 (2017).

    Article  CAS  PubMed  Google Scholar 

  110. Mei, J. et al. Indoleamine 2,3-dioxygenase-1 (IDO1) in human endometrial stromal cells induces macrophage tolerance through interleukin-33 in the progression of endometriosis. Int. J. Clin. Exp. Pathol. 7, 2743–2757 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Wang, Y. et al. Combined 17β-estradiol with TCDD promotes M2 polarization of macrophages in the endometriotic milieu with aid of the interaction between endometrial stromal cells and macrophages. PLoS ONE 10, e0125559 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  112. Bongso, A., Fong, C. Y. & Zhao, H. Q. Effects of peritoneal macrophages from women with endometriosis on endometrial cellular proliferation in an in vitro coculture model. Fertil. Steril. 72, 533–538 (1999).

    Article  PubMed  Google Scholar 

  113. Shao, J. et al. Macrophages promote the growth and invasion of endometrial stromal cells by downregulating IL-24 in endometriosis. Reproduction 152, 673–682 (2016).

    Article  CAS  PubMed  Google Scholar 

  114. Chan, R. W. S., Lee, C. L., Ng, E. H. Y. & Yeung, W. S. B. Co-culture with macrophages enhances the clonogenic and invasion activity of endometriotic stromal cells. Cell Prolif. 50, e12330 (2017).

    Article  PubMed Central  Google Scholar 

  115. Zhou, W.-J., Hou, X.-X., Wang, X.-Q. & Li, D.-J. The CCL17- CCR4 axis between endometrial stromal cells and macrophages contributes to the high levels of IL-6 in ectopic milieu. Am. J. Reprod. Immunol. 78, e12644 (2017).

    Article  Google Scholar 

  116. Mei, J., Zhou, W.-J., Li, S.-Y., Li, M.-Q. & Sun, H.-X. Interleukin-22 secreted by ectopic endometrial stromal cells and natural killer cells promotes the recruitment of macrophages through promoting CCL2 secretion. Am. J. Reprod. Immunol. 82, e13166 (2019).

    Article  PubMed  Google Scholar 

  117. Yu, J.-J. et al. IL15 promotes growth and invasion of endometrial stromal cells and inhibits killing activity of NK cells in endometriosis. Reproduction 152, 151–160 (2016).

    Article  CAS  PubMed  Google Scholar 

  118. Yang, H.-L. et al. The crosstalk between endometrial stromal cells and macrophages impairs cytotoxicity of NK cells in endometriosis by secreting IL-10 and TGF-β. Reproduction 154, 815–825 (2017).

    Article  CAS  PubMed  Google Scholar 

  119. Brueggmann, D. et al. Novel three-dimensional in vitro models of ovarian endometriosis. J. Ovarian Res. 7, 17 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  120. Boretto, M. et al. Patient-derived organoids from endometrial disease capture clinical heterogeneity and are amenable to drug screening. Nat. Cell Biol. 21, 1041–1051 (2019).

    Article  CAS  PubMed  Google Scholar 

  121. Esfandiari, F. et al. Insight into epigenetics of human endometriosis organoids: DNA methylation analysis of HOX genes and their cofactors. Fertil. Steril. 115, 125–137 (2021).

    Article  CAS  PubMed  Google Scholar 

  122. Esfandiari, F. et al. Disturbed progesterone signalling in an advanced preclinical model of endometriosis. Reprod. Biomed. Online 43, 139–147 (2021).

    Article  CAS  PubMed  Google Scholar 

  123. Luddi, A. et al. Organoids of human endometrium: a powerful in vitro model for the endometrium–embryo cross-talk at the implantation site. Cells 9, 1121 (2020).

    Article  CAS  PubMed Central  Google Scholar 

  124. Stejskalova, A. et al. Collagen I triggers directional migration, invasion and matrix remodeling of stroma cells in a 3D spheroid model of endometriosis. Sci. Rep. 11, 4115 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Chen, Z. et al. Co-cultured endometrial stromal cells and peritoneal mesothelial cells for an in vitro model of endometriosis. Integr. Biol. 4, 1090–1095 (2012).

    Article  CAS  Google Scholar 

  126. Chen, C. H. et al. Multiplexed protease activity assay for low-volume clinical samples using droplet-based microfluidics and its application to endometriosis. J. Am. Chem. Soc. 135, 1645–1648 (2013).

    Article  CAS  PubMed  Google Scholar 

  127. Altayyeb, A. et al. Characterization of mechanical signature of eutopic endometrial stromal cells of endometriosis patients. Reprod. Sci. 27, 364–374 (2020).

    Article  CAS  PubMed  Google Scholar 

  128. Kim, J. et al. Acquired contractile ability in human endometrial stromal cells by passive loading of cyclic tensile stretch. Sci. Rep. 10, 9014 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Harada, M. et al. Mechanical stretch stimulates interleukin-8 production in endometrial stromal cells: possible implications in endometrium-related events. J. Clin. Endocrinol. Metab. 90, 1144–1148 (2005).

    Article  CAS  PubMed  Google Scholar 

  130. Harada, M. et al. Mechanical stretch upregulates IGFBP-1 secretion from decidualized endometrial stromal cells. Am. J. Physiol. Endocrinol. Metab. 290, E268–E272 (2006).

    Article  CAS  PubMed  Google Scholar 

  131. Elad, D. et al. Tissue engineered endometrial barrier exposed to peristaltic flow shear stresses. Apl. Bioeng. 4, 26107 (2020).

    Article  CAS  Google Scholar 

  132. Bulletti, C. et al. Characteristics of uterine contractility during menses in women with mild to moderate endometriosis. Fertil. Steril. 77, 1156–1161 (2002).

    Article  PubMed  Google Scholar 

  133. Yu, O. et al. Adenomyosis incidence, prevalence and treatment: United States population-based study 2006–2015. Am. J. Obstet. Gynecol. 223, 94.e1–94.e10 (2020).

    Article  Google Scholar 

  134. An, M. et al. Different macrophages equally induce EMT in endometria of adenomyosis and normal. Reproduction 154, 79–92 (2017).

    Article  CAS  PubMed  Google Scholar 

  135. An, M. et al. Interaction of macrophages and endometrial cells induces epithelial–mesenchymal transition-like processes in adenomyosis. Biol. Reprod. 96, 46–57 (2017).

    PubMed  Google Scholar 

  136. Wang, B., Yang, Y., Deng, X., Ban, Y. & Chao, L. Interaction of M2 macrophages and endometrial cells induces downregulation of GRIM-19 in endometria of adenomyosis. Reprod. BioMedicine Online 41, 790–800 (2020).

    Article  CAS  Google Scholar 

  137. Mehasseb, M. K., Taylor, A. H., Pringle, J. H., Bell, S. C. & Habiba, M. Enhanced invasion of stromal cells from adenomyosis in a three-dimensional coculture model is augmented by the presence of myocytes from affected uteri. Fertil. Steril. 94, 2547–2551 (2010).

    Article  CAS  PubMed  Google Scholar 

  138. Taylor, A. H., Kalathy, V. & Habiba, M. Estradiol and tamoxifen enhance invasion of endometrial stromal cells in a three-dimensional coculture model of adenomyosis. Fertil. Steril. 101, 288–293 (2014).

    Article  CAS  PubMed  Google Scholar 

  139. Gnecco, J. S. et al. Physiomimetic models of adenomyosis. Semin. Reprod. Med. 38, 179–196 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  140. Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2018. CA Cancer J. Clin. 68, 7–30 (2018).

    Article  PubMed  Google Scholar 

  141. Lortet-Tieulent, J., Ferlay, J., Bray, F. & Jemal, A. International patterns and trends in endometrial cancer incidence, 1978–2013. J. Natl Cancer Inst. 110, 354–361 (2018).

    Article  PubMed  Google Scholar 

  142. Gallup, D. G. & Stock, R. J. Adenocarcinoma of the endometrium in women 40 years of age or younger. Obstet. Gynecol. 64, 417–420 (1984).

    CAS  PubMed  Google Scholar 

  143. Cancer Genome Atlas Research, N. et al. Integrated genomic characterization of endometrial carcinoma. Nature 497, 67–73 (2013).

    Article  Google Scholar 

  144. Van Nyen, T., Moiola, C. P., Colas, E., Annibali, D. & Amant, F. Modeling endometrial cancer: past, present, and future. Int. J. Mol. Sci. 19, 2348 (2018).

    Article  PubMed Central  Google Scholar 

  145. Skok, K. et al. Endometrial cancer and its cell lines. Mol. Biol. Rep. 47, 1399–1411 (2020).

    Article  CAS  PubMed  Google Scholar 

  146. Friel, A. M. et al. Mouse models of uterine corpus tumors: clinical significance and utility. Front. Biosci. 2, 882–905 (2010).

    Google Scholar 

  147. Girda, E., Huang, E. C., Leiserowitz, G. S. & Smith, L. H. The use of endometrial cancer patient-derived organoid culture for drug sensitivity testing is feasible. Int. J. Gynecol. Cancer 27, 1701–1707 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  148. Maru, Y., Tanaka, N., Itami, M. & Hippo, Y. Efficient use of patient-derived organoids as a preclinical model for gynecologic tumors. Gynecol. Oncol. 154, 189–198 (2019).

    Article  CAS  PubMed  Google Scholar 

  149. Tamura, H. et al. Evaluation of anticancer agents using patient-derived tumor organoids characteristically similar to source tissues. Oncol. Rep. 40, 635–646 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Chitcholtan, K., Sykes, P. H. & Evans, J. J. The resistance of intracellular mediators to doxorubicin and cisplatin are distinct in 3D and 2D endometrial cancer. J. Transl. Med. 10, 38 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Bi, J. et al. Successful patient-derived organoid culture of gynecologic cancers for disease modeling and drug sensitivity testing. Cancers 13, 2901 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Chen, J. et al. An organoid-based drug screening identified a menin-MLL inhibitor for endometrial cancer through regulating the HIF pathway. Cancer Gene Ther. 28, 112–125 (2020).

    Article  PubMed  Google Scholar 

  153. Jeon, J. S. et al. Human 3D vascularized organotypic microfluidic assays to study breast cancer cell extravasation. Proc. Natl Acad. Sci. USA 112, 214–219 (2015).

    Article  CAS  PubMed  Google Scholar 

  154. Saha, B. et al. OvCa-Chip microsystem recreates vascular endothelium-mediated platelet extravasation in ovarian cancer. Blood Adv. 4, 3329–3342 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Liu, Y. & Cao, X. Characteristics and significance of the pre-metastatic niche. Cancer Cell 30, 668–681 (2016).

    Article  CAS  PubMed  Google Scholar 

  156. Laschke, M. W. & Menger, M. D. Basic mechanisms of vascularization in endometriosis and their clinical implications. Hum. Reprod. Update 24, 207–224 (2018).

    Article  CAS  PubMed  Google Scholar 

  157. Yetkin-Arik, B. et al. Angiogenesis in gynecological cancers and the options for anti-angiogenesis therapy. Biochim. Biophys. Acta Rev. Cancer 1875, 188446 (2021).

    Article  CAS  PubMed  Google Scholar 

  158. Campo, H. et al. Tissue-specific decellularized endometrial substratum mimicking different physiological conditions influences in vitro embryo development in a rabbit model. Acta Biomater. 89, 126–138 (2019).

    Article  CAS  PubMed  Google Scholar 

  159. Hernandez-Gordillo, V. et al. Fully synthetic matrices for in vitro culture of primary human intestinal enteroids and endometrial organoids. Biomaterials 254, 120125 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Alawadhi, F., Du, H., Cakmak, H. & Taylor, H. S. Bone marrow-derived stem cell (BMDSC) transplantation improves fertility in a murine model of Asherman’s syndrome. PLoS ONE 9, e96662 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  161. Taniguchi, F., Wibisono, H., Mon Khine, Y. & Harada, T. Animal models for research on endometriosis. Front. Biosci. 13, 37–53 (2021).

    Article  Google Scholar 

  162. Marquardt, R. M., Jeong, J. W. & Fazleabas, A. T. Animal models of adenomyosis. Semin. Reprod. Med. 38, 168–178 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Bruner-Tran, K. L., Mokshagundam, S., Herington, J. L., Ding, T. & Osteen, K. G. Rodent models of experimental endometriosis: identifying mechanisms of disease and therapeutic targets. Curr. Women’s Health Rev. 14, 173–188 (2018).

    Article  CAS  Google Scholar 

  164. Bazoobandi, S. et al. Induction of Asherman’s syndrome in rabbit. J. Reprod. Infertil. 17, 10–16 (2016).

    PubMed  PubMed Central  Google Scholar 

  165. Feng, Q. et al. Establishment of an animal model of intrauterine adhesions after surgical abortion and curettage in pregnant rats. Ann. Transl. Med. 8, 56 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  166. Merrill, J. A. Spontaneous endometriosis in the Kenya baboon (Papio doguera). Am. J. Obstet. Gynecol. 101, 569–570 (1968).

    Article  CAS  PubMed  Google Scholar 

  167. D’Hooghe, T. M. & Debrock, S. Endometriosis, retrograde menstruation and peritoneal inflammation in women and in baboons. Hum. Reprod. Update 8, 84–88 (2002).

    Article  PubMed  Google Scholar 

  168. Fazleabas, A. T., Brudney, A., Gurates, B., Chai, D. & Bulun, S. A modified baboon model for endometriosis. Ann. N. Y. Acad. Sci. 955, 308–317 (2002).

    Article  PubMed  Google Scholar 

  169. Vernon, M. W. & Wilson, E. A. Studies on the surgical induction of endometriosis in the rat. Fertil. Steril. 44, 684–694 (1985).

    Article  CAS  PubMed  Google Scholar 

  170. Kim, T. H. et al. Activated AKT pathway promotes establishment of endometriosis. Endocrinology 155, 1921–1930 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  171. Eaton, J. L., Unno, K., Caraveo, M., Lu, Z. & Kim, J. J. Increased AKT or MEK1/2 activity influences progesterone receptor levels and localization in endometriosis. J. Clin. Endocrinol. Metab. 98, E1871–E1879 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Habiba, M. In Uterine Adenomyosis (eds Habiba, M. & Benagiano, G.) (Springer International Publishing, 2016).

  173. Daikoku, T. et al. Conditional loss of uterine Pten unfailingly and rapidly induces endometrial cancer in mice. Cancer Res. 68, 5619–5627 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Maru, Y. & Hippo, Y. Two-way development of the genetic model for endometrial tumorigenesis in mice: current and future perspectives. Front. Genet. 12, 798628 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Moiola, C. P. et al. Patient-derived xenograft models for endometrial cancer research. Int. J. Mol. Sci. 19, 2431 (2018).

    Article  PubMed Central  Google Scholar 

  176. Collins, A. et al. Patient-derived explants, xenografts and organoids: 3-dimensional patient-relevant pre-clinical models in endometrial cancer. Gynecol. Oncol. 156, 251–259 (2020).

    Article  CAS  PubMed  Google Scholar 

  177. Bonazzi, V. F. et al. Patient-derived xenograft models capture genomic heterogeneity in endometrial cancer. Genome Med. 14, 3 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Unno, K. et al. Establishment of human patient-derived endometrial cancer xenografts in NOD scid gamma mice for the study of invasion and metastasis. PLoS ONE 9, e116064 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  179. Deligdisch, L. Hormonal pathology of the endometrium. Mod. Pathol. 13, 285–294 (2000).

    Article  CAS  PubMed  Google Scholar 

  180. Guttinger, A. & Critchley, H. O. Endometrial effects of intrauterine levonorgestrel. Contraception 75, S93–S98 (2007).

    Article  CAS  PubMed  Google Scholar 

  181. Mihm, M., Gangooly, S. & Muttukrishna, S. The normal menstrual cycle in women. Anim. Reprod. Sci. 124, 229–236 (2011).

    Article  CAS  PubMed  Google Scholar 

  182. Taran, F. A., Stewart, E. A. & Brucker, S. Adenomyosis: epidemiology, risk factors, clinical phenotype and surgical and interventional alternatives to hysterectomy. Geburtshilfe Frauenheilkd. 73, 924–931 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Mowers, E. L. et al. Prevalence of endometriosis during abdominal or laparoscopic hysterectomy for chronic pelvic pain. Obstet. Gynecol. 127, 1045–1053 (2016).

    Article  PubMed  Google Scholar 

  184. Miyazaki, K. et al. Generation of progesterone-responsive endometrial stromal fibroblasts from human induced pluripotent stem cells: role of the WNT/CTNNB1 pathway. Stem Cell Rep. 11, 1136–1155 (2018).

    Article  CAS  Google Scholar 

  185. Cheung, V. C. et al. Pluripotent stem cell-derived endometrial stromal fibroblasts in a cyclic, hormone-responsive, coculture model of human decidua. Cell Rep. 35, 109138 (2021).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to J. Julie Kim.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Endocrinology thanks Caroline Gargett, Virginia Pensabene and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Organoids

3D cellular aggregates that self-assemble and form structural units that partially resemble the organ in both structure and function.

Microphysiological systems

Integrative, microfabricated platforms designed to recapitulate functional units of human organs in vitro; also known as organ-on-a-chip technology.

Thermoplastics

A class of polymer that can be permanently deformed through the application of heat.

Curettage

Scraping or removal of endometrial tissue for diagnostic or therapeutic purposes.

Spheroids

3D, simple clusters of cells that lack self-assembly or organization.

Sampson’s retrograde menstruation theory

Theory to explain the aetiology of endometriosis in which retrograde flow of sloughed endometrial cells during menstruation occurs through the fallopian tubes into the pelvic cavity promoting the establishment of ectopic lesions.

Chorioallantoic membrane

(CAM). A membrane in bird eggs that is the site of gas exchange for the embryo.

Transwell

A commercially available Boyden chamber device with a microporous membrane that inserts into a standard cell culture well and provides a second compartment.

Micropatterned

Seeding and controlling the geometry and location of cells at the microscale level.

Müllerian remnants

Pluripotent remains of the embryonic precursor to the uterus, which could undergo metaplasia into endometrial tissue during the development of adenomyosis.

Biobanking

Creating a repository of biological samples for use in future research.

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Murphy, A.R., Campo, H. & Kim, J.J. Strategies for modelling endometrial diseases. Nat Rev Endocrinol 18, 727–743 (2022). https://doi.org/10.1038/s41574-022-00725-z

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41574-022-00725-z

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing