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A brief history of testicular organoids: from theory to the wards

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Abstract

In recent years, researchers have successfully generated many human and mammalian organoid models, including organoids representing the intestine, prostate, ovary, bladder, liver, and brain. Therefore, organoids have become an important research model in the fields of regenerative medicine, drug research, and gene therapy, acting as a bridge between in vivo and in vitro experiments. In addition, testicular organoids (TOs) represent the highest level of in vitro culture of spermatogenic cells in a simulated testicular environment. However, the generation of TOs is still in the early stages, and there is still much room for improvement in dealing with the many challenges and prospects to achieve the goal of TOs that simulate the testicular microenvironment in vitro or even reconstruct the process of spermatogenesis without the need to reconstruct seminiferous tubules. We review the brief history of TO generation and some major strategies for functional applications of TOs, which are the main concerns of our clinicians and laboratory researchers.

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References

  1. Lancaster MA, Knoblich JA. Organogenesis in a dish: modeling development and disease using organoid technologies. Science. 2014;345(6194):1247125. https://doi.org/10.1126/science.1247125.

    Article  CAS  PubMed  Google Scholar 

  2. DE SatoStange T, Ferrante M, Vries RG, Van Es JH, Van den Brink S, et al. Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett’s epithelium. Gastroenterology. 2011;141(5):1762–72. https://doi.org/10.1053/j.gastro.2011.07.050.

    Article  CAS  Google Scholar 

  3. Gao D, Vela I, Sboner A, Iaquinta PJ, Karthaus WR, Gopalan A, et al. Organoid cultures derived from patients with advanced prostate cancer. Cell. 2014;159(1):176–87. https://doi.org/10.1016/j.cell.2014.08.016.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Clevers H. Modeling development and disease with organoids. Cell. 2016;165(7):1586–97. https://doi.org/10.1016/j.cell.2016.05.082.

    Article  CAS  PubMed  Google Scholar 

  5. Lancaster MA, Huch M. Disease modelling in human organoids. Dis Model Mech. 2019;12(7). https://doi.org/10.1242/dmm.039347

  6. Takebe T, Wells JM. Organoids by design. Science. 2019;364(6444):956–9. https://doi.org/10.1126/science.aaw7567.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Crespo M, Vilar E, Tsai SY, Chang K, Amin S, Srinivasan T, et al. Colonic organoids derived from human induced pluripotent stem cells for modeling colorectal cancer and drug testing. Nat Med. 2017;23(7):878–84. https://doi.org/10.1038/nm.4355.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Forsythe SD, Devarasetty M, Shupe T, Bishop C, Atala A, Soker S, et al. Environmental toxin screening using human-derived 3D bioengineered liver and cardiac organoids. Front Public Health. 2018;6:103. https://doi.org/10.3389/fpubh.2018.00103.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Francies HE, Barthorpe A, McLaren-Douglas A, Barendt WJ, Garnett MJ. Drug sensitivity assays of human cancer organoid cultures. In: Turksen K, editor. Organoids: stem cells, structure, and function. New York, NY: Springer New York; 2019. p. 339–51

  10. Baert Y, Ruetschle I, Cools W, Oehme A, Lorenz A, Marx U, et al. A multi-organ-chip co-culture of liver and testis equivalents: a first step toward a systemic male reprotoxicity model. Hum Reprod. 2020;35(5):1029–44. https://doi.org/10.1093/humrep/deaa057.

    Article  CAS  PubMed  Google Scholar 

  11. Rajan SAP, Aleman J, Wan M, Pourhabibi Zarandi N, Nzou G, Murphy S, et al. Probing prodrug metabolism and reciprocal toxicity with an integrated and humanized multi-tissue organ-on-a-chip platform. Acta Biomater. 2020;106:124–35. https://doi.org/10.1016/j.actbio.2020.02.015

  12. Skardal A, Aleman J, Forsythe S, Rajan S, Murphy S, Devarasetty M, et al. Drug compound screening in single and integrated multi-organoid body-on-a-chip systems. Biofabrication. 2020;12(2):025017. https://doi.org/10.1088/1758-5090/ab6d36

  13. Park SE, Georgescu A, Huh D. Organoids-on-a-chip Science. 2019;364(6444):960–5. https://doi.org/10.1126/science.aaw7894.

    Article  CAS  PubMed  Google Scholar 

  14. Drost J, van Boxtel R, Blokzijl F, Mizutani T, Sasaki N, Sasselli V, et al. Use of CRISPR-modified human stem cell organoids to study the origin of mutational signatures in cancer. Science (New York, NY). 2017;358(6360):234–8. https://doi.org/10.1126/science.aao3130.

    Article  CAS  Google Scholar 

  15. Liu H-C, Xie Y, Deng C-H, Liu G-H. Stem cell-based therapies for fertility preservation in males: current status and future prospects. World journal of stem cells. 2020;12(10):1097–112. https://doi.org/10.4252/wjsc.v12.i10.1097 (PubMed PMID: 33178394).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Baert Y, De Kock J, Alves-Lopes JP, Soder O, Stukenborg JB, Goossens E. Primary human testicular cells self-organize into organoids with testicular properties. Stem Cell Reports. 2017;8(1):30–8. https://doi.org/10.1016/j.stemcr.2016.11.012.

    Article  CAS  PubMed  Google Scholar 

  17. Kanbar M, Vermeulen M, Wyns C. Organoids as tools to investigate the molecular mechanisms of male infertility and its treatments. Reproduction (Cambridge, England). 2021;161(5):R103–12. https://doi.org/10.1530/REP-20-0499 (PubMed PMID: 33651710).

    Article  CAS  Google Scholar 

  18. Pendergraft SS, Sadri-Ardekani H, Atala A, Bishop CE. Three-dimensional testicular organoid: a novel tool for the study of human spermatogenesis and gonadotoxicity in vitro. Biol Reprod. 2017;96(3):720–32. https://doi.org/10.1095/biolreprod.116.143446.

    Article  PubMed  Google Scholar 

  19. Vlachogiannis G, Hedayat S, Vatsiou A, Jamin Y, Fernandez-Mateos J, Khan K, et al. Patient-derived organoids model treatment response of metastatic gastrointestinal cancers. Science. 2018;359(6378):920–6. https://doi.org/10.1126/science.aao2774.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Oliver E, Alves-Lopes JP, Harteveld F, Mitchell RT, Akesson E, Soder O, et al. Self-organising human gonads generated by a Matrigel-based gradient system. BMC Biol. 2021;19(1):212. https://doi.org/10.1186/s12915-021-01149-3

  21. Alves-Lopes JP, Soder O, Stukenborg JB. Testicular organoid generation by a novel in vitro three-layer gradient system. Biomaterials. 2017;130:76–89. https://doi.org/10.1016/j.biomaterials.2017.03.025.

    Article  CAS  PubMed  Google Scholar 

  22. Alves-Lopes JP, Soder O, Stukenborg JB. Use of a three-layer gradient system of cells for rat testicular organoid generation. Nat Protoc. 2018;13(2):248–59. https://doi.org/10.1038/nprot.2017.140.

    Article  CAS  PubMed  Google Scholar 

  23. Vermeulen M, Del Vento F, Kanbar M, Pyr Dit Ruys S, Vertommen D, Poels J, et al. Generation of organized porcine testicular organoids in solubilized hydrogels from decellularized extracellular matrix. Int J Mol Sci. 2019;20(21). https://doi.org/10.3390/ijms20215476

  24. Rezaei Topraggaleh T, Rezazadeh Valojerdi M, Montazeri L, Baharvand H. A testis-derived macroporous 3D scaffold as a platform for the generation of mouse testicular organoids. Biomater Sci. 2019;7(4):1422–36. https://doi.org/10.1039/c8bm01001c

  25. Sakib S, Uchida A, Valenzuela-Leon P, Yu Y, Valli-Pulaski H, Orwig K, et al. Formation of organotypic testicular organoids in microwell culturedagger. Biol Reprod. 2019;100(6):1648–60. https://doi.org/10.1093/biolre/ioz053.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Goldsmith TM, Sakib S, Webster D, Carlson DF, Van der Hoorn F, Dobrinski I. A reduction of primary cilia but not hedgehog signaling disrupts morphogenesis in testicular organoids. Cell Tissue Res. 2020;380(1):191–200. https://doi.org/10.1007/s00441-019-03121-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Edmonds ME, Woodruff TK. Testicular organoid formation is a property of immature somatic cells, which self-assemble and exhibit long-term hormone-responsive endocrine function. Biofabrication. 2020;12(4):045002. https://doi.org/10.1088/1758-5090/ab9907

  28. Rore H, Owen N, Pina-Aguilar RE, Docherty K, Sekido R. Testicular somatic cell-like cells derived from embryonic stem cells induce differentiation of epiblasts into germ cells. Commun Biol. 2021;4(1):802. https://doi.org/10.1038/s42003-021-02322-8

  29. Pryzhkova MV, Jordan PW. Adaptation of human testicular niche cells for pluripotent stem cell and testis development research. Tissue Eng Regen Med. 2020;17(2):223–35. https://doi.org/10.1007/s13770-020-00240-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Chen G, Bei B, Feng Y, Li X, Jiang Z, Si JY, et al. Glycyrrhetinic acid maintains intestinal homeostasis via HuR. Front Pharmacol. 2019;10:535. https://doi.org/10.3389/fphar.2019.00535

  31. Aloia L, McKie MA, Vernaz G, Cordero-Espinoza L, Aleksieva N, van den Ameele J, et al. Epigenetic remodelling licences adult cholangiocytes for organoid formation and liver regeneration. Nature cell biology. 2019;21(11):1321–33. https://doi.org/10.1038/s41556-019-0402-6

  32. Strange DP, Zarandi NP, Trivedi G, Atala A, Bishop CE, Sadri-Ardekani H, et al. Human testicular organoid system as a novel tool to study Zika virus pathogenesis. Emerg Microbes Infect. 2018;7(1):82. https://doi.org/10.1038/s41426-018-0080-7

  33. Alves-Lopes JP, Stukenborg JB. Testicular organoids: a new model to study the testicular microenvironment in vitro? Hum Reprod Update. 2018;24(2):176–91. https://doi.org/10.1093/humupd/dmx036.

    Article  CAS  PubMed  Google Scholar 

  34. Drost J, van Jaarsveld RH, Ponsioen B, Zimberlin C, van Boxtel R, Buijs A, et al. Sequential cancer mutations in cultured human intestinal stem cells. Nature. 2015;521(7550):43–7. https://doi.org/10.1038/nature14415.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank all our comrades and friends for their support related to this work.

Funding

This research was supported by the National Key Research and Development Program of China (2018YFC1005002), the National Key Research and Development Program of China (2018YFC1004900), and The Family Planning Program of Military Medical Innovation Project of PLA (18JS003).

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Contributions

WANG Nengzhuang, SHEN Jiaming, LIU Minghua, MA Long, QIN Lina, GE Xuemei, and YAN Hongli designed this paper; WANG Nengzhuang wrote the paper and made the picture; WANG Nengzhuang and SHEN Jiaming revised the paper. All authors have read and approved the final manuscript.

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Correspondence to G. E. Xuemei or Y. A. N. Hongli.

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All authors named have participated in the work in a substantive way and are prepared to take public responsibility for the work. The manuscript being submitted to this journal has never been published and that it is not being submitted for publication elsewhere. The authors declare no competing interests.

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Nengzhuang, W., Jiaming, S., Minghua, L.I.U. et al. A brief history of testicular organoids: from theory to the wards. J Assist Reprod Genet 39, 1423–1431 (2022). https://doi.org/10.1007/s10815-022-02529-6

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