Skip to main content

Advertisement

SpringerLink
Log in

Human Female Reproductive System Organoids: Applications in Developmental Biology, Disease Modelling, and Drug Discovery

  • Published:
Stem Cell Reviews and Reports Aims and scope Submit manuscript

Abstract

Organoid technique has achieved significant progress in recent years, owing to the rapid development of the three-dimensional (3D) culture techniques in adult stem cells (ASCs) and pluripotent stem cells (PSCs) that are capable of self-renewal and induced differentiation. However, our understanding of human female reproductive system organoids is in its infancy. Recently, scientists have established self-organizing 3D organoids for human endometrium, fallopian tubes, oocyte, and trophoblasts by culturing stem cells with a cocktail of cytokines in a 3D scaffold. These organoids express multicellular biomarkers and show functional characteristics similar to those of their origin organs, which provide potential avenues to explore reproductive system development, disease modelling, and patient-specific therapy. Nevertheless, advanced culture methods, such as co-culture system, 3D bioprinting and organoid-on-a-chip technology, remain to be explored, and more efforts should be made for further elucidation of cell–cell crosstalk. This review describes the development and applications of human female reproductive system organoids.

Figure: Applications in developmental biology, disease modelling, and drug discovery of human female reproductive system organoids. ASCs: adult stem cells; PSCs: pluripotent stem cells.

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

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Giuliana, R., Andrea, M., & Lutolf, M. P. (2018). Progress and potential in organoid research. Nature Reviews Genetics, 19, 671–687.

    Google Scholar 

  2. Kai, K., & Hans, C. (2016). Organoids: Modeling development and the stem cell niche in a dish. Developmental Cell, 38, 590–600.

    Google Scholar 

  3. Turco, M. Y., Lucy, G., Jasmine, H., et al. (2017). Long-term, hormone-responsive organoid cultures of human endometrium in a chemically defined medium. Nature Cell Biology, 19, 568–577.

    PubMed  PubMed Central  CAS  Google Scholar 

  4. Sandra, H., Gudrun, M., Leila, S., et al. (2018). Self-renewing trophoblast organoids recapitulate the developmental program of the early human placenta. Stem Cell Reports, 11, 537–551.

    Google Scholar 

  5. Lancaster, M. A., & Knoblich, J. A. (2014). Organogenesis in a dish: Modeling development and disease using organoid technologies. Science, 345, 1247125.

    PubMed  Google Scholar 

  6. Kazutoshi, T., Koji, T., Mari, O., et al. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell, 131, 861–872.

    Google Scholar 

  7. In-Hyun, P., Natasha, A., Hongguang, H., et al. (2008). Disease-specific induced pluripotent stem cells. Cell, 134, 877–886.

    Google Scholar 

  8. Narasimman, G., Abdulrhman, A., Sheeja, R., et al. (2018). Adult stem cells for regenerative therapy. Progress in Molecular Biology and Translational Science, 160, 1–22.

    Google Scholar 

  9. Youssef, H., & Anis, F. (2020). Organoid models of human endometrial development and disease. Frontiers in Cell and Developmental Biology, 8, 84.

    Google Scholar 

  10. Thomson, J. A., Itskovitz-Eldor, J., Shapiro, S., et al. (1998). Embryonic stem cell lines derived from human blastocysts. Science, 282, 1145–1147.

    PubMed  CAS  Google Scholar 

  11. Mototsugu, E., Nozomu, T., Hiroki, I., et al. (2011). Self-organizing optic-cup morphogenesis in three-dimensional culture. Nature, 472, 51–56.

    Google Scholar 

  12. Toshiro, S., Vries, R. G., Snippert, H. J., et al. (2009). Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature, 459, 262–265.

    Google Scholar 

  13. Rinehart, C. A., Lyn-Cook, B. D., & Kaufman, D. G. (1988). Gland formation from human endometrial epithelial cells in vitro. In Vitro Cellular & Developmental Biology, 24, 1037–1041.

    Google Scholar 

  14. Bläuer, M., Heinonen, P. K., Martikainen, P. M., Tomás, E., & Ylikomi, T. (2005). A novel organotypic culture model for normal human endometrium: Regulation of epithelial cell proliferation by estradiol and medroxyprogesterone acetate. Human Reproduction, 20, 864–871.

    PubMed  Google Scholar 

  15. Nguyen, H. P. T., Xiao, L., Deane, J. A., et al. (2017). N-cadherin identifies human endometrial epithelial progenitor cells by in vitro stem cell assays. Human Reproduction, 32, 2254–2268.

    PubMed  CAS  Google Scholar 

  16. Fitzgerald, H. C., Dhakal, P., Behura, S. K., et al. (2019). Self-renewing endometrial epithelial organoids of the human uterus. Proceedings of the National Academy of Sciences of the United States of America, 116, 23132–23142.

    PubMed  PubMed Central  CAS  Google Scholar 

  17. Valentijn, A. J., Saretzki, G., Tempest, N., Critchley, H. O., & Hapangama, D. K. (2015). Human endometrial epithelial telomerase is important for epithelial proliferation and glandular formation with potential implications in endometriosis. Human Reproduction, 30, 2816–2828.

    PubMed  CAS  Google Scholar 

  18. Syed, S. M., Kumar, M., Ghosh, A., et al. (2020). Endometrial axin2 cells drive epithelial homeostasis, regeneration, and cancer following oncogenic transformation. Cell Stem Cell, 26, 64–80.e13.

    PubMed  CAS  Google Scholar 

  19. Sandra, H., Magdalena, G., Burkard, T. R., et al. (2019). Estrogen signaling drives ciliogenesis in human endometrial organoids. Endocrinology, 160, 2282–2297.

    Google Scholar 

  20. Murphy, A. R., Teerawat, W., Lu, Z., et al. (2019). Generation of multicellular human primary endometrial organoids. Journal of Visualized Experiments, 152. https://doi.org/10.3791/60384.

  21. Bishop, E. A., Stan, L., Elangovan, T., et al. (2014). Insulin exerts direct effects on carcinogenic transformation of human endometrial organotypic cultures. Cancer Investigation, 32, 63–70.

    PubMed  CAS  Google Scholar 

  22. Paweł, Ł., Gomez, A., Hire, G., et al. (2017). Human three-dimensional endometrial epithelial cell model to study host interactions with vaginal bacteria and Neisseria gonorrhoeae. Infection and Immunity, 85, e01049-16.

    Google Scholar 

  23. Benbrook, D. M., Stan, L., James, R.-M., et al. (2008). Gene expression analysis of biological systems driving an organotypic model of endometrial carcinogenesis and chemoprevention. Gene Regulation and Systems Biology, 2, 21–42.

    PubMed  PubMed Central  CAS  Google Scholar 

  24. Kamelle, S., Sienko, A., & Benbrook, D. M. (2002). Retinoids and steroids regulate menstrual phase histological features in human endometrial organotypic cultures. Fertility and Sterility, 78, 596–602.

    PubMed  Google Scholar 

  25. Fayazi, M., Salehnia, M., & Ziaei, S. (2017). In-vitro construction of endometrial-like epithelium using CD146 mesenchymal cells derived from human endometrium. Reproductive Biomedicine Online, 35, 241–252.

    PubMed  CAS  Google Scholar 

  26. Johnson, M. H. (2017). First evidence that endometrial-like organoids can develop from the endometrial mesenchymal stem/stromal cell population. Reproductive Biomedicine Online, 35, 239–240.

    PubMed  Google Scholar 

  27. Wiwatpanit, T., Murphy, A. R., Lu, Z., et al. (2020). Scaffold-free endometrial organoids respond to excess androgens associated with polycystic ovarian syndrome. The Journal of Clinical Endocrinology and Metabolism, 105, 769–780.

    Google Scholar 

  28. Boretto, M., Maenhoudt, N., Luo, X., et al. (2019). Patient-derived organoids from endometrial disease capture clinical heterogeneity and are amenable to drug screening. Nature Cell Biology, 21, 1041–1051.

    PubMed  CAS  Google Scholar 

  29. Classen-Linke, I., Kusche, M., Knauthe, R., & Beier, H. M. (1997). Establishment of a human endometrial cell culture system and characterization of its polarized hormone responsive epithelial cells. Cell and Tissue Research, 287, 171–185.

    PubMed  CAS  Google Scholar 

  30. Yang, H., Sungwon, H., Haekwon, K., et al. (2002). Expression of integrins, cyclooxygenases and matrix metalloproteinases in three-dimensional human endometrial cell culture system. Experimental & Molecular Medicine, 34, 75–82.

    CAS  Google Scholar 

  31. Aurélie, H., Katharina, H., Matteo, B., et al. (2019). Functional expression of the mechanosensitive PIEZO1 channel in primary endometrial epithelial cells and endometrial organoids. Scientific Reports, 9, 1779.

    Google Scholar 

  32. Barros, F. S. V. (2017). Characterization of human endometrial glandular epithelium in vitro and in vivo (pp. 1–252). Warwick: Division of Biomedical Sciences Warwick Medical School University of Warwick.

    Google Scholar 

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

    PubMed  CAS  Google Scholar 

  34. Hapangama, D. K., Drury, J., Da Silva, L., et al. (2019). Abnormally located SSEA1+/SOX9+ endometrial epithelial cells with a basalis-like phenotype in the eutopic functionalis layer may play a role in the pathogenesis of endometriosis. Human Reproduction, 34, 56–68.

    PubMed  CAS  Google Scholar 

  35. Łaniewski, P., & Herbst-Kralovetz, M. M. (1997). Analysis of host responses to Neisseria gonorrhoeae using a human three-dimensional endometrial epithelial cell model. Methods in Molecular Biology, 2019, 347–361.

    Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  37. Miyazaki, K., Dyson, M. T., Coon, V., John, S., et al. (2018). Generation of progesterone-responsive endometrial stromal fibroblasts from human induced pluripotent stem cells: Role of the WNT/CTNNB1 pathway. Stem Cell Reports, 11, 1136–1155.

    PubMed  PubMed Central  CAS  Google Scholar 

  38. Kessler, M., Hoffmann, K., Brinkmann, V., et al. (2015). The Notch and Wnt pathways regulate stemness and differentiation in human fallopian tube organoids. Nature Communications, 6, 8989.

    PubMed  PubMed Central  CAS  Google Scholar 

  39. Yucer, N., Holzapfel, M., Vogel, T. J., et al. (2017). Directed differentiation of human induced pluripotent stem cells into fallopian tube epithelium. Scientific Reports, 7, 10741.

    PubMed  PubMed Central  Google Scholar 

  40. Lawrenson, K., Notaridou, M., Lee, N., et al. (2013). In vitro three-dimensional modeling of fallopian tube secretory epithelial cells. BMC Cell Biology, 14, 43.

    PubMed  PubMed Central  CAS  Google Scholar 

  41. Kessler, M., Hoffmann, K., Fritsche, K., et al. (2019). Chronic Chlamydia infection in human organoids increases stemness and promotes age-dependent CpG methylation. Nature Communications, 10, 1194.

    PubMed  PubMed Central  Google Scholar 

  42. Yu-Hsun, C., Tang-Yuan, C., & Dah-Ching, D. (2020). Human fallopian tube epithelial cells exhibit stemness features, self-renewal capacity, and Wnt-related organoid formation. Journal of Biomedical Science, 27, 32.

    Google Scholar 

  43. Turco, M. Y., Gardner, L., Kay, R. G., et al. (2018). Trophoblast organoids as a model for maternal-fetal interactions during human placentation. Nature, 564, 263–267.

    PubMed  PubMed Central  CAS  Google Scholar 

  44. Li, Z., Kurosawa, O., & Iwata, H. (2018). Development of trophoblast cystic structures from human induced pluripotent stem cells in limited-area cell culture. Biochemical and Biophysical Research Communications, 505, 671–676.

    PubMed  CAS  Google Scholar 

  45. Dajung, J., Xiong, J., Min, Y., et al. (2017). In vitro differentiation of human embryonic stem cells into ovarian follicle-like cells. Nature Communications, 8, 15680.

    Google Scholar 

  46. Lawrenson, K., Benjamin, E., Turmaine, M., Jacobs, I., Gayther, S., & Dafou, D. (2009). In vitro three-dimensional modelling of human ovarian surface epithelial cells. Cell Proliferation, 42, 385–393.

    PubMed  PubMed Central  CAS  Google Scholar 

  47. Ohtake, H., Katabuchi, H., Matsuura, K., et al. (1999). A novel in vitro experimental model for ovarian endometriosis: The three-dimensional culture of human ovarian surface epithelial cells in collagen gels. Fertility and Sterility, 71, 50–55.

    PubMed  CAS  Google Scholar 

  48. Girda, E., Huang, E. C., Leiserowitz, G. S., et al. (2017). The use of endometrial cancer patient-derived organoid culture for drug sensitivity testing is feasible. The International Journal of Gynecological Cancer, 27, 1701–1707.

    PubMed  Google Scholar 

  49. Shuang, Z., Igor, D., Tao, Z., et al. (2019). Both fallopian tube and ovarian surface epithelium are cells-of-origin for high-grade serous ovarian carcinoma. Nature Communications, 10, 5367.

    Google Scholar 

  50. Paik, D. Y., Janzen, D. M., Schafenacker, A. M., et al. (2012). Stem-like epithelial cells are concentrated in the distal end of the fallopian tube: A site for injury and serous cancer initiation. Stem Cells, 30, 2487–2497.

    PubMed  PubMed Central  CAS  Google Scholar 

  51. Abbas, Y., Oefner, C. M., Polacheck, W. J., et al. (2017). A microfluidics assay to study invasion of human placental trophoblast cells. The Journal of the Royal Society Interface, 14, 20170131.

    Google Scholar 

  52. Ma, L., Li, G., Cao, G., et al. (2017). dNK cells facilitate the interaction between trophoblastic and endothelial cells via VEGF-C and HGF. Immunology and Cell Biology, 95, 695–704.

    PubMed  CAS  Google Scholar 

  53. McConkey, C. A., Delorme-Axford, E., Nickerson, C. A., et al. (2016). A three-dimensional culture system recapitulates placental syncytiotrophoblast development and microbial resistance. Science Advances, 2, e1501462.

    PubMed  PubMed Central  Google Scholar 

  54. Kotomi, S., Yasuhisa, M., Michiya, S., et al. (2018). Aggregation of human trophoblast cells into three-dimensional culture system enhances anti-inflammatory characteristics through cytoskeleton regulation. The International Journal of Molecular Sciences, 19, 2322.

    Google Scholar 

  55. Wong, M. K., Shawky, S. A., Aryasomayajula, A., et al. (2018). Extracellular matrix surface regulates self-assembly of three-dimensional placental trophoblast spheroids. PLoS One, 13, e199632.

    Google Scholar 

  56. Kalkunte, S., Huang, Z., Lippe, E., et al. (2017). Polychlorinated biphenyls target Notch/Dll and VEGF R2 in the mouse placenta and human trophoblast cell lines for their anti-angiogenic effects. Scientific Reports, 7, 39885.

    PubMed  PubMed Central  CAS  Google Scholar 

  57. Nhan, P., Hong, J. J., Tofig, B., et al. (2019). A simple high-throughput approach identifies actionable drug sensitivities in patient-derived tumor organoids. Communications Biology, 2, 78.

    Google Scholar 

  58. Jabs, J., Zickgraf, F. M., Park, J., et al. (2017). Screening drug effects in patient-derived cancer cells links organoid responses to genome alterations. Molecular Systems Biology, 13, 955.

    PubMed  PubMed Central  Google Scholar 

  59. Moore, C. A., Shah, N. N., Smith, C. P., et al. (1842). 3D bioprinting and stem cells. Methods in Molecular Biology, 2018, 93–103.

    Google Scholar 

  60. Zhang, Y. S., Arneri, A., Bersini, S., et al. (2016). Bioprinting 3D microfibrous scaffolds for engineering endothelialized myocardium and heart-on-a-chip. Biomaterials, 110, 45–59.

    PubMed  PubMed Central  CAS  Google Scholar 

  61. Han, F., Utkan, D., & Pu, C. (2019). Emerging organoid models: leaping forward in cancer research. Journal of Hematology & Oncology, 12, 142.

    Google Scholar 

  62. Mittal, R., Woo, F. W., Castro, C. S., et al. (2019). Organ-on-chip models: Implications in drug discovery and clinical applications. Journal of Cellular Physiology, 234, 8352–8380.

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

No funding or financial support has been received.

No manuscript preparation assistance was provided or paid for.

All persons who contributed to the work reported in the manuscript are included as authors.

The contents of this manuscript have never been presented at a meeting.

No earlier version of this manuscript has been published on a preprint server.

All tables and figures are original, and no material has been adapted or modified from another source.

Disclaimer

The ideas and opinions expressed herein are those of the authors. The views expressed in the review are those of the authors and do not necessarily reflect the official policy or position of the Department of Maternal and Child Health of the National Health and Family Planning Commission of the People’s Republic of China.

Contributors

All authors contributed to the conception and design of this review. Cui drafted the first version of the article, and Zhao, Wu, and Li revised it critically for important intellectual content. Final approval of the version to be published was given by all authors.

Author information

Author notes

  1. The first two authors should be regarded as joint first authors and contributed equally

Authors and Affiliations

  1. Obstetrics and Gynaecology Hospital of Fudan University, Shanghai, China

    Yutong Cui, Huanqiang Zhao, Suwen Wu & Xiaotian Li

  2. Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Fudan University, Shanghai, China

    Xiaotian Li

  3. Institute of Biomedical Sciences, Fudan University, Shanghai, China

    Xiaotian Li

Authors
  1. Yutong Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Huanqiang Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Suwen Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xiaotian Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xiaotian Li.

Ethics declarations

Conflict of Interest Disclosures

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cui, Y., Zhao, H., Wu, S. et al. Human Female Reproductive System Organoids: Applications in Developmental Biology, Disease Modelling, and Drug Discovery. Stem Cell Rev and Rep 16, 1173–1184 (2020). https://doi.org/10.1007/s12015-020-10039-0

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12015-020-10039-0

Keywords

Search

Navigation