Endometrial Organoids and Their Role in Modeling Human Infertility
Abstract
:1. Introduction
2. Endometrial Receptivity and Implantation
3. Development, Structure, and Formation Methods of Organoids
4. Organoid Transplantation as a Therapeutic Strategy for Infertility
5. Endometrial Organoids as Models for Infertility and Endometrial Diseases
5.1. Endometriosis
5.2. Endometrial Dysfunction
5.3. Asherman’s Syndrome
5.4. Endometrial Cancer
5.5. Endometrial Infection
5.6. Environmental and Drug-Induced Toxicity
6. Impact of Organoids on Assisted Reproductive Technologies (ARTs) and Biomarker Development
7. Biomarker Development
8. Current Limitations and Future Insights of Endometrial Organoids
8.1. Technological Limitations
8.2. Biological Constraints
8.3. Translational Barriers in Endometrial Organoid Transplantation (EOT)
8.4. Ethical Considerations
9. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
References
- Corrò, C.; Novellasdemunt, L.; Li, V.S.W. A Brief History of Organoids. Am. J. Physiol. Cell Physiol. 2020, 319, C151–C165. [Google Scholar] [CrossRef] [PubMed]
- Sato, T.; Vries, R.G.; Snippert, H.J.; van de Wetering, M.; Barker, N.; Stange, D.E.; van Es, J.H.; Abo, A.; Kujala, P.; Peters, P.J.; et al. Single Lgr5 Stem Cells Build Crypt-Villus Structures in Vitro without a Mesenchymal Niche. Nature 2009, 459, 262–265. [Google Scholar] [CrossRef] [PubMed]
- Wilson, H.V. A New Method by Which Sponges May Be Artificially Reared. Science 1907, 25, 912–915. [Google Scholar] [CrossRef] [PubMed]
- Jabri, A.; Khan, J.; Taftafa, B.; Alsharif, M.; Mhannayeh, A.; Chinnappan, R.; Alzhrani, A.; Kazmi, S.; Mir, M.S.; Alsaud, A.W.; et al. Bioengineered Organoids Offer New Possibilities for Liver Cancer Studies: A Review of Key Milestones and Challenges. Bioengineering 2024, 11, 346. [Google Scholar] [CrossRef]
- Smirnova, L.; Hartung, T. The Promise and Potential of Brain Organoids. Adv. Healthc. Mater. 2024, 13, e2302745. [Google Scholar] [CrossRef]
- Guo, J.; Zhou, W.; Sacco, M.; Downing, P.; Dimitriadis, E.; Zhao, F. Using Organoids to Investigate Human Endometrial Receptivity. Front. Endocrinol. 2023, 14, 1158515. [Google Scholar] [CrossRef]
- Critchley, H.O.D.; Maybin, J.A.; Armstrong, G.M.; Williams, A.R.W. Physiology of the Endometrium and Regulation of Menstruation. Physiol. Rev. 2020, 100, 1149–1179. [Google Scholar] [CrossRef]
- Abady, M.M.; Saadeldin, I.M.; Han, A.; Bang, S.; Kang, H.; Seok, D.W.; Kwon, H.-J.; Cho, J.; Jeong, J.-S. Melatonin and Resveratrol Alleviate Molecular and Metabolic Toxicity Induced by Bisphenol A in Endometrial Organoids. Reprod. Toxicol. 2024, 128, 108628. [Google Scholar] [CrossRef]
- Lessey, B.A.; Young, S.L. What Exactly Is Endometrial Receptivity? Fertil. Steril. 2019, 111, 611–617. [Google Scholar] [CrossRef]
- Governini, L.; Luongo, F.P.; Haxhiu, A.; Piomboni, P.; Luddi, A. Main Actors behind the Endometrial Receptivity and Successful Implantation. Tissue Cell 2021, 73, 101656. [Google Scholar] [CrossRef]
- Turco, M.Y.; Gardner, L.; Hughes, J.; Cindrova-Davies, T.; Gomez, M.J.; Farrell, L.; Hollinshead, M.; Marsh, S.G.E.; Brosens, J.J.; Critchley, H.O.; et al. Long-Term, Hormone-Responsive Organoid Cultures of Human Endometrium in a Chemically Defined Medium. Nat. Cell Biol. 2017, 19, 568–577. [Google Scholar] [CrossRef] [PubMed]
- Bhagwat, S.R.; Redij, T.; Phalnikar, K.; Nayak, S.; Iyer, S.; Gadkar, S.; Chaudhari, U.; Kholkute, S.D.; Sachdeva, G. Cell Surfactomes of Two Endometrial Epithelial Cell Lines That Differ in Their Adhesiveness to Embryonic Cells. Mol. Reprod. Dev. 2014, 81, 326–340. [Google Scholar] [CrossRef] [PubMed]
- Juárez-Barber, E.; Segura-Benítez, M.; Carbajo-García, M.C.; Bas-Rivas, A.; Faus, A.; Vidal, C.; Giles, J.; Labarta, E.; Pellicer, A.; Cervelló, I.; et al. Extracellular Vesicles Secreted by Adenomyosis Endometrial Organoids Contain MiRNAs Involved in Embryo Implantation and Pregnancy. Reprod. Biomed. Online 2023, 46, 470–481. [Google Scholar] [CrossRef] [PubMed]
- Kagawa, H.; Javali, A.; Khoei, H.H.; Sommer, T.M.; Sestini, G.; Novatchkova, M.; Scholte Op Reimer, Y.; Castel, G.; Bruneau, A.; Maenhoudt, N.; et al. Human Blastoids Model Blastocyst Development and Implantation. Nature 2022, 601, 600–605. [Google Scholar] [CrossRef]
- Boretto, M.; Maenhoudt, N.; Luo, X.; Hennes, A.; Boeckx, B.; Bui, B.; Heremans, R.; Perneel, L.; Kobayashi, H.; Van Zundert, I.; et al. Patient-Derived Organoids from Endometrial Disease Capture Clinical Heterogeneity and Are Amenable to Drug Screening. Nat. Cell Biol. 2019, 21, 1041–1051. [Google Scholar] [CrossRef]
- Hwang, S.-Y.; Lee, D.; Lee, G.; Ahn, J.; Lee, Y.-G.; Koo, H.S.; Kang, Y.-J. Endometrial Organoids: A Reservoir of Functional Mitochondria for Uterine Repair. Theranostics 2024, 14, 954–972. [Google Scholar] [CrossRef]
- Tamura, H.; Higa, A.; Hoshi, H.; Hiyama, G.; Takahashi, N.; Ryufuku, M.; Morisawa, G.; Yanagisawa, Y.; Ito, E.; Imai, J.-I.; et al. Evaluation of Anticancer Agents Using Patient-Derived Tumor Organoids Characteristically Similar to Source Tissues. Oncol. Rep. 2018, 40, 635–646. [Google Scholar] [CrossRef]
- Cindrova-Davies, T.; Zhao, X.; Elder, K.; Jones, C.J.P.; Moffett, A.; Burton, G.J.; Turco, M.Y. Menstrual Flow as a Non-Invasive Source of Endometrial Organoids. Commun. Biol. 2021, 4, 651. [Google Scholar] [CrossRef]
- Marinić, M.; Rana, S.; Lynch, V.J. Derivation of Endometrial Gland Organoids from Term Placenta. Placenta 2020, 101, 75–79. [Google Scholar] [CrossRef]
- Saadeldin, I.M.; Ehab, S.; Noreldin, A.E.; Swelum, A.A.-A.; Bang, S.; Kim, H.; Yoon, K.Y.; Lee, S.; Cho, J. Current Strategies Using 3D Organoids to Establish in Vitro Maternal-Embryonic Interaction. J. Vet. Sci. 2024, 25, e40. [Google Scholar] [CrossRef]
- Boretto, M.; Cox, B.; Noben, M.; Hendriks, N.; Fassbender, A.; Roose, H.; Amant, F.; Timmerman, D.; Tomassetti, C.; Vanhie, A.; et al. Development of Organoids from Mouse and Human Endometrium Showing Endometrial Epithelium Physiology and Long-Term Expandability. Development 2017, 144, 1775–1786. [Google Scholar] [CrossRef] [PubMed]
- Syed, S.M.; Kumar, M.; Ghosh, A.; Tomasetig, F.; Ali, A.; Whan, R.M.; Alterman, D.; Tanwar, P.S. Endometrial Axin2+ Cells Drive Epithelial Homeostasis, Regeneration, and Cancer Following Oncogenic Transformation. Cell Stem Cell 2020, 26, 64–80.e13. [Google Scholar] [CrossRef] [PubMed]
- Santos, C.P.; Lapi, E.; Martínez de Villarreal, J.; Álvaro-Espinosa, L.; Fernández-Barral, A.; Barbáchano, A.; Domínguez, O.; Laughney, A.M.; Megías, D.; Muñoz, A.; et al. Urothelial Organoids Originating from Cd49fhigh Mouse Stem Cells Display Notch-Dependent Differentiation Capacity. Nat. Commun. 2019, 10, 4407. [Google Scholar] [CrossRef] [PubMed]
- Wang, X.; Ni, C.; Jiang, N.; Wei, J.; Liang, J.; Zhao, B.; Lin, X. Generation of Liver Bipotential Organoids with a Small-Molecule Cocktail. J. Mol. Cell Biol. 2020, 12, 618–629. [Google Scholar] [CrossRef]
- Haider, S.; Gamperl, M.; Burkard, T.R.; Kunihs, V.; Kaindl, U.; Junttila, S.; Fiala, C.; Schmidt, K.; Mendjan, S.; Knöfler, M.; et al. Estrogen Signaling Drives Ciliogenesis in Human Endometrial Organoids. Endocrinology 2019, 160, 2282–2297. [Google Scholar] [CrossRef]
- Bates, R.C.; Mercurio, A.M. Tumor Necrosis Factor-Alpha Stimulates the Epithelial-to-Mesenchymal Transition of Human Colonic Organoids. Mol. Biol. Cell 2003, 14, 1790–1800. [Google Scholar] [CrossRef]
- Tojo, M.; Hamashima, Y.; Hanyu, A.; Kajimoto, T.; Saitoh, M.; Miyazono, K.; Node, M.; Imamura, T. The ALK-5 Inhibitor A-83-01 Inhibits Smad Signaling and Epithelial-to-Mesenchymal Transition by Transforming Growth Factor-Beta. Cancer Sci. 2005, 96, 791–800. [Google Scholar] [CrossRef]
- Cui, X.; Shang, S.; Lv, X.; Zhao, J.; Qi, Y.; Liu, Z. Perspectives of Small Molecule Inhibitors of Activin Receptor-like Kinase in Anti-tumor Treatment and Stem Cell Differentiation (Review). Mol. Med. Rep. 2019, 19, 5053–5062. [Google Scholar] [CrossRef]
- Kuijk, E.W.; Rasmussen, S.; Blokzijl, F.; Huch, M.; Gehart, H.; Toonen, P.; Begthel, H.; Clevers, H.; Geurts, A.M.; Cuppen, E. Generation and Characterization of Rat Liver Stem Cell Lines and Their Engraftment in a Rat Model of Liver Failure. Sci. Rep. 2016, 6, 22154. [Google Scholar] [CrossRef]
- Urbischek, M.; Rannikmae, H.; Foets, T.; Ravn, K.; Hyvönen, M.; de la Roche, M. Organoid Culture Media Formulated with Growth Factors of Defined Cellular Activity. Sci. Rep. 2019, 9, 6193. [Google Scholar] [CrossRef]
- Phan-Everson, T.; Etoc, F.; Li, S.; Khodursky, S.; Yoney, A.; Brivanlou, A.H.; Siggia, E.D. Differential Compartmentalization of BMP4/NOGGIN Requires NOGGIN Trans-Epithelial Transport. Dev. Cell 2021, 56, 1930–1944.e5. [Google Scholar] [CrossRef] [PubMed]
- Nikolakopoulou, K.; Turco, M.Y. Investigation of Infertility Using Endometrial Organoids. Reproduction 2021, 161, R113–R127. [Google Scholar] [CrossRef] [PubMed]
- Garcia-Alonso, L.; Handfield, L.-F.; Roberts, K.; Nikolakopoulou, K.; Fernando, R.C.; Gardner, L.; Woodhams, B.; Arutyunyan, A.; Polanski, K.; Hoo, R.; et al. Mapping the Temporal and Spatial Dynamics of the Human Endometrium in Vivo and in Vitro. Nat. Genet. 2021, 53, 1698–1711. [Google Scholar] [CrossRef] [PubMed]
- Nguyen, H.P.T.; Xiao, L.; Deane, J.A.; Tan, K.-S.; Cousins, F.L.; Masuda, H.; Sprung, C.N.; Rosamilia, A.; Gargett, C.E. N-Cadherin Identifies Human Endometrial Epithelial Progenitor Cells by in Vitro Stem Cell Assays. Hum. Reprod. 2017, 32, 2254–2268. [Google Scholar] [CrossRef]
- Valentijn, A.J.; Palial, K.; Al-Lamee, H.; Tempest, N.; Drury, J.; Von Zglinicki, T.; Saretzki, G.; Murray, P.; Gargett, C.E.; Hapangama, D.K. SSEA-1 Isolates Human Endometrial Basal Glandular Epithelial Cells: Phenotypic and Functional Characterization and Implications in the Pathogenesis of Endometriosis. Hum. Reprod. 2013, 28, 2695–2708. [Google Scholar] [CrossRef]
- Wiwatpanit, T.; Murphy, A.R.; Lu, Z.; Urbanek, M.; Burdette, J.E.; Woodruff, T.K.; Kim, J.J. Scaffold-Free Endometrial Organoids Respond to Excess Androgens Associated with Polycystic Ovarian Syndrome. J. Clin. Endocrinol. Metab. 2020, 105, 769–780. [Google Scholar] [CrossRef]
- Shibata, S.; Endo, S.; Nagai, L.A.E.; Kobayashi, E.H.; Oike, A.; Kobayashi, N.; Kitamura, A.; Hori, T.; Nashimoto, Y.; Nakato, R.; et al. Modeling Embryo-Endometrial Interface Recapitulating Human Embryo Implantation. Sci. Adv. 2024, 10, eadi4819. [Google Scholar] [CrossRef]
- Aplin, J.D.; Charlton, A.K.; Ayad, S. An Immunohistochemical Study of Human Endometrial Extracellular Matrix during the Menstrual Cycle and First Trimester of Pregnancy. Cell Tissue Res. 1988, 253, 231–240. [Google Scholar] [CrossRef]
- Iwahashi, M.; Muragaki, Y.; Ooshima, A.; Yamoto, M.; Nakano, R. Alterations in Distribution and Composition of the Extracellular Matrix during Decidualization of the Human Endometrium. J. Reprod. Fertil. 1996, 108, 147–155. [Google Scholar] [CrossRef]
- Oefner, C.M.; Sharkey, A.; Gardner, L.; Critchley, H.; Oyen, M.; Moffett, A. Collagen Type IV at the Fetal-Maternal Interface. Placenta 2015, 36, 59–68. [Google Scholar] [CrossRef]
- Abbas, Y.; Carnicer-Lombarte, A.; Gardner, L.; Thomas, J.; Brosens, J.J.; Moffett, A.; Sharkey, A.M.; Franze, K.; Burton, G.J.; Oyen, M.L. Tissue Stiffness at the Human Maternal-Fetal Interface. Hum. Reprod. 2019, 34, 1999–2008. [Google Scholar] [CrossRef] [PubMed]
- Rawlings, T.M.; Makwana, K.; Taylor, D.M.; Molè, M.A.; Fishwick, K.J.; Tryfonos, M.; Odendaal, J.; Hawkes, A.; Zernicka-Goetz, M.; Hartshorne, G.M.; et al. Modelling the Impact of Decidual Senescence on Embryo Implantation in Human Endometrial Assembloids. Elife 2021, 10, e69603. [Google Scholar] [CrossRef] [PubMed]
- Below, C.R.; Kelly, J.; Brown, A.; Humphries, J.D.; Hutton, C.; Xu, J.; Lee, B.Y.; Cintas, C.; Zhang, X.; Hernandez-Gordillo, V.; et al. A Microenvironment-Inspired Synthetic Three-Dimensional Model for Pancreatic Ductal Adenocarcinoma Organoids. Nat. Mater. 2022, 21, 110–119. [Google Scholar] [CrossRef] [PubMed]
- Sugawara, J.; Fukaya, T.; Murakami, T.; Yoshida, H.; Yajima, A. Increased Secretion of Hepatocyte Growth Factor by Eutopic Endometrial Stromal Cells in Women with Endometriosis. Fertil. Steril. 1997, 68, 468–472. [Google Scholar] [CrossRef]
- Chen, C.; Spencer, T.E.; Bazer, F.W. Fibroblast Growth Factor-10: A Stromal Mediator of Epithelial Function in the Ovine Uterus. Biol. Reprod. 2000, 63, 959–966. [Google Scholar] [CrossRef]
- Chung, D.; Gao, F.; Jegga, A.G.; Das, S.K. Estrogen Mediated Epithelial Proliferation in the Uterus Is Directed by Stromal Fgf10 and Bmp8a. Mol. Cell Endocrinol. 2015, 400, 48–60. [Google Scholar] [CrossRef]
- Cha, E.; Choi, Y.S.; Lee, M.J.; Kim, M.; Seo, S.J.; Kwak, S.M.; Park, S.; Cho, S.; Jin, Y. Uterus-Mimetic Extracellular Microenvironment for Engineering Female Reproductive System. Adv. Funct. Mater. 2025, 35, 2415149. [Google Scholar] [CrossRef]
- Dai, Y.; Zhao, F.; Zhang, S.; Chen, Q.; Zeng, B.; Wang, X.; Gu, W.; Zhang, Y.; Lin, X.; Liu, N.; et al. Engineering Vascularized Human Endometrial Organoids for In Vivo Tissue Regeneration and Repair Applications. Hum. Reprod. 2024, 39, deae108.054. [Google Scholar] [CrossRef]
- Gong, L.; Nie, N.; Shen, X.; Zhang, J.; Li, Y.; Liu, Y.; Xu, J.; Jiang, W.; Liu, Y.; Liu, H.; et al. Bi-Potential HPSC-Derived Müllerian Duct-like Cells for Full-Thickness and Functional Endometrium Regeneration. npj Regen. Med. 2022, 7, 68. [Google Scholar] [CrossRef]
- He, W.; Zhu, X.; Xin, A.; Zhang, H.; Sun, Y.; Xu, H.; Li, H.; Yang, T.; Zhou, D.; Yan, H.; et al. Long-Term Maintenance of Human Endometrial Epithelial Stem Cells and Their Therapeutic Effects on Intrauterine Adhesion. Cell Biosci. 2022, 12, 175. [Google Scholar] [CrossRef]
- Zhang, H.; Xu, D.; Li, Y.; Lan, J.; Zhu, Y.; Cao, J.; Hu, M.; Yuan, J.; Jin, H.; Li, G.; et al. Organoid Transplantation Can Improve Reproductive Prognosis by Promoting Endometrial Repair in Mice. Int. J. Biol. Sci. 2022, 18, 2627–2638. [Google Scholar] [CrossRef] [PubMed]
- Domnina, A.; Novikova, P.; Obidina, J.; Fridlyanskaya, I.; Alekseenko, L.; Kozhukharova, I.; Lyublinskaya, O.; Zenin, V.; Nikolsky, N. Human Mesenchymal Stem Cells in Spheroids Improve Fertility in Model Animals with Damaged Endometrium. Stem Cell Res. Ther. 2018, 9, 50. [Google Scholar] [CrossRef] [PubMed]
- Wiweko, B. Intrauterine Medical Therapies (i.e.: PRP Infusions, G-CSF). Fertil. Reprod. 2023, 5, 292. [Google Scholar] [CrossRef]
- Park, S.-R.; Kim, S.-R.; Im, J.B.; Park, C.H.; Lee, H.-Y.; Hong, I.-S. 3D Stem Cell-Laden Artificial Endometrium: Successful Endometrial Regeneration and Pregnancy. Biofabrication 2021, 13, 045012. [Google Scholar] [CrossRef] [PubMed]
- Carson, S.A.; Kallen, A.N. Diagnosis and Management of Infertility: A Review. JAMA 2021, 326, 65–76. [Google Scholar] [CrossRef]
- Unuane, D.; Tournaye, H.; Velkeniers, B.; Poppe, K. Endocrine Disorders & Female Infertility. Best Pract. Res. Clin. Endocrinol. Metab. 2011, 25, 861–873. [Google Scholar] [CrossRef]
- Story, L.; Kennedy, S. Animal Studies in Endometriosis: A Review. ILAR J. 2004, 45, 132–138. [Google Scholar] [CrossRef]
- Carter, A.M. Animal Models of Human Placentation—A Review. Placenta 2007, 28, S41–S47. [Google Scholar] [CrossRef]
- Bulun, S.E.; Yilmaz, B.D.; Sison, C.; Miyazaki, K.; Bernardi, L.; Liu, S.; Kohlmeier, A.; Yin, P.; Milad, M.; Wei, J. Endometriosis. Endocr. Rev. 2019, 40, 1048–1079. [Google Scholar] [CrossRef]
- Moradi, Y.; Shams-Beyranvand, M.; Khateri, S.; Gharahjeh, S.; Tehrani, S.; Varse, F.; Tiyuri, A.; Najmi, Z. A Systematic Review on the Prevalence of Endometriosis in Women. Indian J. Med. Res. 2021, 154, 446–454. [Google Scholar] [CrossRef]
- Brueggmann, D.; Templeman, C.; Starzinski-Powitz, A.; Rao, N.P.; Gayther, S.A.; Lawrenson, K. Novel Three-Dimensional in Vitro Models of Ovarian Endometriosis. J. Ovarian Res. 2014, 7, 17. [Google Scholar] [CrossRef] [PubMed]
- Esfandiari, F.; Favaedi, R.; Heidari-Khoei, H.; Chitsazian, F.; Yari, S.; Piryaei, A.; Ghafari, F.; Baharvand, H.; Shahhoseini, M. Insight into Epigenetics of Human Endometriosis Organoids: DNA Methylation Analysis of HOX Genes and Their Cofactors. Fertil. Steril. 2021, 115, 125–137. [Google Scholar] [CrossRef] [PubMed]
- Esfandiari, F.; Heidari Khoei, H.; Saber, M.; Favaedi, R.; Piryaei, A.; Moini, A.; Shahhoseini, M.; Ramezanali, F.; Ghaffari, F.; Baharvand, H. Disturbed Progesterone Signalling in an Advanced Preclinical Model of Endometriosis. Reprod. Biomed. Online 2021, 43, 139–147. [Google Scholar] [CrossRef] [PubMed]
- Bui, B.N.; Boretto, M.; Kobayashi, H.; van Hoesel, M.; Steba, G.S.; van Hoogenhuijze, N.; Broekmans, F.J.M.; Vankelecom, H.; Torrance, H.L. Organoids Can Be Established Reliably from Cryopreserved Biopsy Catheter-Derived Endometrial Tissue of Infertile Women. Reprod. Biomed. Online 2020, 41, 465–473. [Google Scholar] [CrossRef]
- Bastu, E.; Demiral, I.; Gunel, T.; Ulgen, E.; Gumusoglu, E.; Hosseini, M.K.; Sezerman, U.; Buyru, F.; Yeh, J. Potential Marker Pathways in the Endometrium That May Cause Recurrent Implantation Failure. Reprod. Sci. 2019, 26, 879–890. [Google Scholar] [CrossRef]
- Devesa-Peiro, A.; Sebastian-Leon, P.; Garcia-Garcia, F.; Arnau, V.; Aleman, A.; Pellicer, A.; Diaz-Gimeno, P. Uterine Disorders Affecting Female Fertility: What Are the Molecular Functions Altered in Endometrium? Fertil. Steril. 2020, 113, 1261–1274. [Google Scholar] [CrossRef]
- Bui, B.N.; Ardisasmita, A.I.; van de Vliert, F.H.; Abendroth, M.S.; van Hoesel, M.; Mackens, S.; Fuchs, S.A.; Nieuwenhuis, E.E.S.; Broekmans, F.J.M.; Steba, G.S. Enrichment of Cell Cycle Pathways in Progesterone-Treated Endometrial Organoids of Infertile Women Compared to Fertile Women. J. Assist. Reprod. Genet. 2024, 41, 2405–2418. [Google Scholar] [CrossRef]
- Koot, Y.E.M.; van Hooff, S.R.; Boomsma, C.M.; van Leenen, D.; Groot Koerkamp, M.J.A.; Goddijn, M.; Eijkemans, M.J.C.; Fauser, B.C.J.M.; Holstege, F.C.P.; Macklon, N.S. An Endometrial Gene Expression Signature Accurately Predicts Recurrent Implantation Failure after IVF. Sci. Rep. 2016, 6, 19411. [Google Scholar] [CrossRef]
- Dreisler, E.; Kjer, J.J. Asherman’s Syndrome: Current Perspectives on Diagnosis and Management. Int. J. Womens Health 2019, 11, 191–198. [Google Scholar] [CrossRef]
- Santamaria, X.; Roson, B.; Perez-Moraga, R.; Venkatesan, N.; Pardo-Figuerez, M.; Gonzalez-Fernandez, J.; Llera-Oyola, J.; Fernández, E.; Moreno, I.; Salumets, A.; et al. Decoding the Endometrial Niche of Asherman’s Syndrome at Single-Cell Resolution. Nat. Commun. 2023, 14, 5890. [Google Scholar] [CrossRef]
- Jiang, X.; Li, X.; Fei, X.; Shen, J.; Chen, J.; Guo, M.; Li, Y. Endometrial Membrane Organoids from Human Embryonic Stem Cell Combined with the 3D Matrigel for Endometrium Regeneration in Asherman Syndrome. Bioact. Mater. 2021, 6, 3935–3946. [Google Scholar] [CrossRef] [PubMed]
- Henley, S.J.; Ward, E.M.; Scott, S.; Ma, J.; Anderson, R.N.; Firth, A.U.; Thomas, C.C.; Islami, F.; Weir, H.K.; Lewis, D.R.; et al. Annual Report to the Nation on the Status of Cancer, Part I: National Cancer Statistics. Cancer 2020, 126, 2225–2249. [Google Scholar] [CrossRef] [PubMed]
- Hibaoui, Y.; Feki, A. Organoid Models of Human Endometrial Development and Disease. Front. Cell Dev. Biol. 2020, 8, 84. [Google Scholar] [CrossRef] [PubMed]
- Chen, X.; Liu, X.; Li, Q.; Lu, B.; Xie, B.; Ji, Y.; Zhao, Y. A Patient-Derived Organoid-Based Study Identified an ASO Targeting SNORD14E for Endometrial Cancer through Reducing Aberrant FOXM1 Expression and β-Catenin Nuclear Accumulation. J. Exp. Clin. Cancer Res. 2023, 42, 230. [Google Scholar] [CrossRef]
- Chen, J.; Dai, S.; Zhao, L.; Peng, Y.; Sun, C.; Peng, H.; Zhong, Q.; Quan, Y.; Li, Y.; Chen, X.; et al. A New Type of Endometrial Cancer Models in Mice Revealing the Functional Roles of Genetic Drivers and Exploring Their Susceptibilities. Adv. Sci. 2023, 10, 2300383. [Google Scholar] [CrossRef]
- Maru, Y.; Tanaka, N.; Itami, M.; Hippo, Y. Efficient Use of Patient-Derived Organoids as a Preclinical Model for Gynecologic Tumors. Gynecol. Oncol. 2019, 154, 189–198. [Google Scholar] [CrossRef]
- Sengal, A.T.; Bonazzi, V.; Smith, D.; Moiola, C.P.; Lourie, R.; Rogers, R.; Colas, E.; Gil-Moreno, A.; Frentzas, S.; Chetty, N.; et al. Endometrial Cancer PDX-Derived Organoids (PDXOs) and PDXs with FGFR2c Isoform Expression Are Sensitive to FGFR Inhibition. npj Precis. Oncol. 2023, 7, 127. [Google Scholar] [CrossRef]
- Bi, J.; Newtson, A.M.; Zhang, Y.; Devor, E.J.; Samuelson, M.I.; Thiel, K.W.; Leslie, K.K. Successful Patient-Derived Organoid Culture of Gynecologic Cancers for Disease Modeling and Drug Sensitivity Testing. Cancers 2021, 13, 2901. [Google Scholar] [CrossRef]
- Girda, E.; Leiserowitz, G.S.; Smith, L.H.; Huang, E.C. The Use of Endometrial Cancer Patient-Derived Organoid Culture for Drug Sensitivity Testing Is Feasible. Int. J. Gynecol. Cancer 2017, 27, 1701–1707. [Google Scholar] [CrossRef]
- Łaniewski, P.; Gomez, A.; Hire, G.; So, M.; Herbst-Kralovetz, M.M. Human Three-Dimensional Endometrial Epithelial Cell Model To Study Host Interactions with Vaginal Bacteria and Neisseria gonorrhoeae. Infect. Immun. 2017, 85, e01049-16. [Google Scholar] [CrossRef]
- Bishop, R.C.; Boretto, M.; Rutkowski, M.R.; Vankelecom, H.; Derré, I. Murine Endometrial Organoids to Model Chlamydia Infection. Front. Cell Infect. Microbiol. 2020, 10, 416. [Google Scholar] [CrossRef] [PubMed]
- Dolat, L.; Valdivia, R.H. An Endometrial Organoid Model of Interactions between Chlamydia and Epithelial and Immune Cells. J. Cell Sci. 2021, 134, jcs252403. [Google Scholar] [CrossRef] [PubMed]
- Abady, M.M.; Jeong, J.-S.; Kwon, H.-J.; Assiri, A.M.; Cho, J.; Saadeldin, I.M. The Reprotoxic Adverse Side Effects of Neurogenic and Neuroprotective Drugs: Current Use of Human Organoid Modeling as a Potential Alternative to Preclinical Models. Front. Pharmacol. 2024, 15, 1412188. [Google Scholar] [CrossRef] [PubMed]
- Nawroth, F.; Ludwig, M. What Is the ‘Ideal’ Duration of Progesterone Supplementation before the Transfer of Cryopreserved–Thawed Embryos in Estrogen/Progesterone Replacement Protocols? Hum. Reprod. 2005, 20, 1127–1134. [Google Scholar] [CrossRef]
- Ma, W.; Song, H.; Das, S.K.; Paria, B.C.; Dey, S.K. Estrogen Is a Critical Determinant That Specifies the Duration of the Window of Uterine Receptivity for Implantation. Proc. Natl. Acad. Sci. USA 2003, 100, 2963–2968. [Google Scholar] [CrossRef]
- Aboulghar, M. Prediction of Ovarian Hyperstimulation Syndrome (OHSS): Estradiol Level Has an Important Role in the Prediction of OHSS. Hum. Reprod. 2003, 18, 1140–1141. [Google Scholar] [CrossRef]
- Liang, Y.-X.; Liu, L.; Jin, Z.-Y.; Liang, X.-H.; Fu, Y.-S.; Gu, X.-W.; Yang, Z.-M. The High Concentration of Progesterone Is Harmful for Endometrial Receptivity and Decidualization. Sci. Rep. 2018, 8, 712. [Google Scholar] [CrossRef]
- Larsen, E.C.; Christiansen, O.B.; Kolte, A.M.; Macklon, N. New Insights into Mechanisms behind Miscarriage. BMC Med. 2013, 11, 154. [Google Scholar] [CrossRef]
- Aghajanova, L. Correction to: How Good Are We at Modeling Implantation? J. Assist. Reprod. Genet. 2020, 37, 1763. [Google Scholar] [CrossRef]
- Rawlings, T.M.; Makwana, K.; Tryfonos, M.; Lucas, E.S. Organoids to Model the Endometrium: Implantation and Beyond. Reprod. Fertil. 2021, 2, R85–R101. [Google Scholar] [CrossRef]
- Kleinová, M.; Varga, I.; Čeháková, M.; Valent, M.; Klein, M. Exploring the Black Box of Human Reproduction: Endometrial Organoids and Assembloids—Generation, Implantation Modeling, and Future Clinical Perspectives. Front. Cell Dev. Biol. 2024, 12, 1482054. [Google Scholar] [CrossRef] [PubMed]
- Gatimel, N.; Bruno, E.; Perez, G.; Sagnat, D.; Rolland, C.; Tanguy-Le-Gac, Y.; Pol, H.; Léandri, R.; Merle, N.; Deraison, C.; et al. O-096 Human Fallopian Tube Organoids Provide a Favorable Environment for Sperm Motility. Hum. Reprod. 2024, 39, deae108-102. [Google Scholar] [CrossRef]
- Barry, F.; Brouillet, S.; Hamamah, S. P-789 Trophoblast Organoids as a 3D Model for the Study of Oxygen Concentration during in Vitro Preimplantation Embryo Culture. Hum. Reprod. 2024, 39, deae108.053. [Google Scholar] [CrossRef]
- Ak, A.; Luijkx, D.; Carvalho, D.; Romano, A.; Stevens-Brentjens, L.; Voncken, W.; Giselbrecht, S.; Van Golde, R.; Vrij, E. O-097 Implantation-on-Chip: Precise Quantification for Functional Implantation Failure Studies. Hum. Reprod. 2024, 39, deae108.103. [Google Scholar] [CrossRef]
- Koler, M.; Achache, H.; Tsafrir, A.; Smith, Y.; Revel, A.; Reich, R. Disrupted Gene Pattern in Patients with Repeated in Vitro Fertilization (IVF) Failure. Hum. Reprod. 2009, 24, 2541–2548. [Google Scholar] [CrossRef]
- Gutsche, S. Seminal Plasma Induces MRNA Expression of IL-1, IL-6 and LIF in Endometrial Epithelial Cells in Vitro. Mol. Hum. Reprod. 2003, 9, 785–791. [Google Scholar] [CrossRef]
- George, A.F.; Jang, K.S.; Nyegaard, M.; Neidleman, J.; Spitzer, T.L.; Xie, G.; Chen, J.C.; Herzig, E.; Laustsen, A.; Marques de Menezes, E.G.; et al. Seminal Plasma Promotes Decidualization of Endometrial Stromal Fibroblasts In Vitro from Women with and without Inflammatory Disorders in a Manner Dependent on Interleukin-11 Signaling. Hum. Reprod. 2020, 35, 617–640. [Google Scholar] [CrossRef]
- Van den Berg, J.; Toros, M.; Abendroth, M.; Arends, B.; Broekmans, F.; Steba, G. O-098 The Transcriptome of Endometrial Organoids of Fertile and Subfertile Women Exposed to Seminal Plasma of Fertile Men. Hum. Reprod. 2024, 39, deae108.104. [Google Scholar] [CrossRef]
- Hirsch, M.S.; Watkins, J. A Comprehensive Review of Biomarker Use in the Gynecologic Tract Including Differential Diagnoses and Diagnostic Pitfalls. Adv. Anat. Pathol. 2020, 27, 164–192. [Google Scholar] [CrossRef]
- Deane, J.A.; Cousins, F.L.; Gargett, C.E. Endometrial Organoids: In Vitro Models for Endometrial Research and Personalized Medicine†. Biol. Reprod. 2017, 97, 781–783. [Google Scholar] [CrossRef]
- Gu, Z.-Y.; Jia, S.-Z.; Liu, S.; Leng, J.-H. Endometrial Organoids: A New Model for the Research of Endometrial-Related Diseases†. Biol. Reprod. 2020, 103, 918–926. [Google Scholar] [CrossRef] [PubMed]
- 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 2019, 116, 23132–23142. [Google Scholar] [CrossRef] [PubMed]
- Gilks, C.B.; Oliva, E.; Soslow, R.A. Poor Interobserver Reproducibility in the Diagnosis of High-Grade Endometrial Carcinoma. Am. J. Surg. Pathol. 2013, 37, 874–881. [Google Scholar] [CrossRef] [PubMed]
- Cochrane, D.R.; Campbell, K.R.; Greening, K.; Ho, G.C.; Hopkins, J.; Bui, M.; Douglas, J.M.; Sharlandjieva, V.; Munzur, A.D.; Lai, D.; et al. Single Cell Transcriptomes of Normal Endometrial Derived Organoids Uncover Novel Cell Type Markers and Cryptic Differentiation of Primary Tumours. J. Pathol. 2020, 252, 201–214. [Google Scholar] [CrossRef]
- Luddi, A.; Pavone, V.; Semplici, B.; Governini, L.; Criscuoli, M.; Paccagnini, E.; Gentile, M.; Morgante, G.; De Leo, V.; Belmonte, G.; et al. Organoids of Human Endometrium: A Powerful In Vitro Model for the Endometrium-Embryo Cross-Talk at the Implantation Site. Cells 2020, 9, 1121. [Google Scholar] [CrossRef]
- Giobbe, G.G.; Crowley, C.; Luni, C.; Campinoti, S.; Khedr, M.; Kretzschmar, K.; De Santis, M.M.; Zambaiti, E.; Michielin, F.; Meran, L.; et al. Extracellular Matrix Hydrogel Derived from Decellularized Tissues Enables Endodermal Organoid Culture. Nat. Commun. 2019, 10, 5658. [Google Scholar] [CrossRef]
- Murphy, A.R.; Wiwatpanit, T.; Lu, Z.; Davaadelger, B.; Kim, J.J. Generation of Multicellular Human Primary Endometrial Organoids. J. Vis. Exp. 2019, 152, 10–3791. [Google Scholar] [CrossRef]
- Abbas, Y.; Brunel, L.G.; Hollinshead, M.S.; Fernando, R.C.; Gardner, L.; Duncan, I.; Moffett, A.; Best, S.; Turco, M.Y.; Burton, G.J.; et al. Generation of a Three-Dimensional Collagen Scaffold-Based Model of the Human Endometrium. Interface Focus 2020, 10, 20190079. [Google Scholar] [CrossRef]
- Simintiras, C.A.; Dhakal, P.; Ranjit, C.; Fitzgerald, H.C.; Balboula, A.Z.; Spencer, T.E. Capture and Metabolomic Analysis of the Human Endometrial Epithelial Organoid Secretome. Proc. Natl. Acad. Sci. USA 2021, 118, e2026804118. [Google Scholar] [CrossRef]
- Co, J.Y.; Margalef-Català, M.; Monack, D.M.; Amieva, M.R. Controlling the Polarity of Human Gastrointestinal Organoids to Investigate Epithelial Biology and Infectious Diseases. Nat. Protoc. 2021, 16, 5171–5192. [Google Scholar] [CrossRef]
- Li, J.-L.; Lin, L.-Q.; Zhong, J.-M.; Li, X.-T.; Lee, C.-L.; Chiu, P.C.N. Organoids as a Model to Study the Human Endometrium. Reprod. Dev. Med. 2022, 6, 215–224. [Google Scholar] [CrossRef]
- Esfandiari, F.; Mansouri, N.; Shahhoseini, M.; Heidari Khoei, H.; Mikaeeli, G.; Vankelecom, H.; Baharvand, H. Endometriosis Organoids: Prospects and Challenges. Reprod. Biomed. Online 2022, 45, 5–9. [Google Scholar] [CrossRef] [PubMed]
- Mylonas, I.; Jeschke, U.; Kunert-Keil, C.; Shabani, N.; Dian, D.; Bauerfeind, I.; Kuhn, C.; Kupka, M.S.; Friese, K. Glycodelin A Is Expressed Differentially in Normal Human Endometrial Tissue throughout the Menstrual Cycle as Assessed by Immunohistochemistry and in Situ Hybridization. Fertil. Steril. 2006, 86, 1488–1497. [Google Scholar] [CrossRef] [PubMed]
- Focarelli, R.; Luddi, A.; De Leo, V.; Capaldo, A.; Stendardi, A.; Pavone, V.; Benincasa, L.; Belmonte, G.; Petraglia, F.; Piomboni, P. Dysregulation of GdA Expression in Endometrium of Women With Endometriosis: Implication for Endometrial Receptivity. Reprod. Sci. 2018, 25, 579–586. [Google Scholar] [CrossRef]
- Orkin, R.W.; Gehron, P.; McGoodwin, E.B.; Martin, G.R.; Valentine, T.; Swarm, R. A Murine Tumor Producing a Matrix of Basement Membrane. J. Exp. Med. 1977, 145, 204–220. [Google Scholar] [CrossRef]
- Rossi, G.; Manfrin, A.; Lutolf, M.P. Progress and Potential in Organoid Research. Nat. Rev. Genet. 2018, 19, 671–687. [Google Scholar] [CrossRef]
- Xiao, S.; Coppeta, J.R.; Rogers, H.B.; Isenberg, B.C.; Zhu, J.; Olalekan, S.A.; McKinnon, K.E.; Dokic, D.; Rashedi, A.S.; Haisenleder, D.J.; et al. A Microfluidic Culture Model of the Human Reproductive Tract and 28-Day Menstrual Cycle. Nat. Commun. 2017, 8, 14584. [Google Scholar] [CrossRef]
- Park, S.-R.; Kim, S.-R.; Lee, J.W.; Park, C.H.; Yu, W.-J.; Lee, S.-J.; Chon, S.J.; Lee, D.H.; Hong, I.-S. Development of a Novel Dual Reproductive Organ on a Chip: Recapitulating Bidirectional Endocrine Crosstalk between the Uterine Endometrium and the Ovary. Biofabrication 2021, 13, 015001. [Google Scholar] [CrossRef]
Study | Organoid Type | Research Focus | Key Findings | Impact | Published in |
---|---|---|---|---|---|
Sato T, et al. (2009) [2] | IO | Organoid formation | Demonstrated that single Lgr5+ intestinal stem cells can generate self-organizing crypt-villus structures | Pioneering study that launched the modern era of organoid research | Nature |
Jabri A, et al. (2024) [4] | LO | Cancer modeling | Reviewed liver cancer organoid development, emphasizing their value for studying hepatocellular carcinoma | Highlights organoid utility in liver cancer research and therapeutic discovery | Bioengineering (Basel) |
Smirnova L, et al. (2024) [5] | BO | Translational neuroscience | Reviewed applications of brain organoids in modeling neurological diseases and drug development | Highlights brain organoids as powerful tools for brain research and personalized medicine | Adv Healthc Mater |
Guo J, et al. (2023) [6] | EO | Endometrial receptivity | Explores how endometrial organoids can be used to study human endometrial receptivity and factors influencing implantation | Contributes to reproductive health by advancing our understanding of implantation and fertility | Front Endocrinol (Lausanne) |
Abady, M. M., et al. (2024) [8] | EO | Toxicology, Reproductive health | Demonstrated the protective effects of melatonin and resveratrol in BPA-induced endometrial toxicity | Advances our understanding of environmental toxins and reproductive health | Reproductive Toxicology |
Turco MY, et al. (2017) [11] | EO | Endometrial culture and hormonal regulation | Developed long-term, hormone-responsive organoid cultures of human endometrium, crucial for studying menstrual cycles and implantation | Provides a model for studying endometrial diseases and infertility | Nat Cell Biol |
Juárez-Barber E, et al. (2023) [13] | EO | Embryo implantation and pregnancy | Identified miRNAs in extracellular vesicles that are involved in embryo implantation and pregnancy, highlighting the potential of organoids for reproductive research | Provides insights into the molecular mechanisms of embryo implantation and pregnancy using endometrial organoids | Reproductive Biomedicine Online |
Boretto M, et al. (2019) [15] | EO | Disease modeling, Drug screening | Patient-derived endometrial organoids were created to capture clinical heterogeneity in endometrial diseases and were used for drug screening | Advances in personalized medicine and drug screening for endometrial diseases | Nat Cell Biol |
Hwang SY, et al. (2024) [16] | EO | Uterine repair | Identified endometrial organoids as a source of functional mitochondria, highlighting their potential in uterine repair and regenerative medicine | Opens new avenues for uterine tissue repair, offering a potential therapeutic strategy for infertility related to uterine dysfunction | Theranostics |
Tamura H, et al. (2018) [17] | PDOs | Evaluation of anticancer agents | Patient-derived tumor organoids were shown to closely resemble the source tissues and can be used to evaluate anticancer agents | Provides a valuable model for personalized cancer therapy by testing drug efficacy on patient-derived organoids | Oncol Rep |
Cindrova-Davies T, et al. (2021) [18] | EO | Non-invasive sources of EO | The study demonstrated that menstrual flow can be a viable source for generating endometrial organoids | Offers a non-invasive method for obtaining endometrial tissue, which could improve research on endometrial diseases | Commun Biol |
Marinić M, et al. (2020) [19] | EGO | Derivation of EGO | Successful derivation of organoids from the term placenta, offering a model to study endometrial function | Provides a new in vitro model for investigating endometrial biology, useful for understanding endometrial and placental interactions | Placenta |
Saadeldin IM, et al. (2024) [20] | HO | Maternal–embryonic interaction | Reviewed 3D organoid models utilized to study the interactions between maternal and embryonic cells in vitro. | Advances understanding of maternal–embryonic communication, providing insights into fertility and implantation. | J Vet Sci |
Boretto M, et al. (2017) [21] | EO | Reproductive biology, Endometrial physiology | Developed human and mouse endometrial organoids, demonstrating endometrial epithelium physiology and long-term expandability | Provides a model for studying endometrial function and related diseases, with potential applications in fertility research | Development |
Santos CP, et al. (2019) [23] | UO | Regenerative medicine | Urothelial organoids display Notch-dependent differentiation capacity, providing insights into urothelial tissue development and regenerative therapies | Advances the understanding of urothelial biology and organoid-based models for regenerative medicine and drug testing | Nat Commun |
Wang X, et al. (2020) [24] | LO | Liver disease modeling | Successful generation of liver bipotential organoids that can differentiate into both hepatocytes and cholangiocytes, providing a model for liver disease modeling and regenerative medicine | Provides a novel organoid model for liver disease research, drug testing, and potential therapeutic applications | J Mol Cell Biol |
Haider S, et al. (2019) [25] | EO | Endometrial diseases | Estrogen signaling was found to drive ciliogenesis in endometrial organoids, shedding light on the hormonal regulation of cilia formation in the endometrium | Advances understanding of estrogen’s role in the endometrium, with potential implications for fertility and endometrial diseases | Endocrinology |
Bates RC, et al. (2003) [26] | HO | Epithelial tumors | TNF-α was found to induce EMT in human colonic organoids, a key process in cancer metastasis | Provides insight into the mechanisms of metastasis and the role of inflammation in promoting EMT, relevant for cancer research | Mol Biol Cell |
Nikolakopoulou K, et al. (2021) [32] | EO | Infertility and reproductive health | Focused on how endometrial organoids are used to investigate infertility, with an emphasis on embryo implantation | Provides insights into the use of organoids for studying fertility issues and endometrial function | Reproduction |
Garcia-Alonso L, et al. (2021) [33] | EO | Infertility | Mapping of the endometrial dynamics to understand its role in fertility and diseases | Provides valuable insights into endometrial biology and could improve disease modeling and therapeutic strategies | Nat Genet |
Wiwatpanit T, et al. (2020) [36] | EO | PCOS | Demonstrated that scaffold-free endometrial organoids respond to excess androgens, a hallmark of PCOS, revealing potential mechanisms of disease | Contributes to understanding the pathophysiology of PCOS and could inform therapeutic strategies for managing androgen excess and related reproductive issues | J Clin Endocrinol Metab |
Shibata S, et al. (2024) [37] | EO | Embryo–endometrial interface | Developed a model to study the embryo–endometrial interface, recapitulating human embryo implantation in vitro | Provides new insights into the molecular interactions during embryo implantation, offering potential for fertility treatments | Sci Adv |
Cha E, et al. (2024) [47] | EO | Endometrial diseases | UEM supports endometrial organoid development more effectively than Matrigel; decorin in UEM enhances Wnt7a expression; UEM improves epithelial regeneration and pregnancy rates in vivo | Provides a biomimetic scaffold that enhances organoid development and has potential therapeutic applications in endometrial regeneration | Advanced Functional Materials |
Dai Y, et al. (2024) [48] | EO | Organoid development | Successfully engineered vascularized endometrial organoids that integrate with host tissue, promoting regeneration and repair in vivo | Demonstrates the potential of vascularized organoids in endometrial tissue engineering and regenerative medicine | Human Reproduction |
Gong L, et al. (2022) [49] | hPSC-MuDO | Regenerative medicine | Successfully generated hPSC-derived Müllerian duct-like organoids capable of differentiating into both epithelial and stromal lineages, leading to the regeneration of full-thickness endometrial tissue in vivo | Demonstrates the potential of hPSC-derived organoids in endometrial tissue engineering and regenerative medicine | npj Regenerative Medicine |
He et al., (2022) [50] | MDO | Organoid development | SSEA-1+ cells self-organized into organoid structures with long-term expansion capacity; transplantation in a rat IUA model reduced fibrosis and facilitated endometrial regeneration | Demonstrates the potential of stem cell-derived organoids in endometrial regeneration and treatment of IUA | Cell and Bioscience |
Zhang H, et al. (2022) [51] | EO | Organoid transplantation | Organoid transplantation improved endometrial repair and reproductive prognosis in mice | Highlights potential for organoid-based therapies in endometrial regeneration and fertility restoration | Int J Biol Sci |
Jiang X, et al. (2021) [71] | EO | Endometrial diseases | Successful regeneration of endometrial tissue using stem cell-derived organoids and 3D Matrigel in Asherman syndrome | Demonstrates the potential of organoids in treating endometrial damage and infertility | Bioact Mater |
Wiweko B. (2023) [53] | EO | Infertility, Regenerative medicine | Intrauterine PRP shows promise in improving implantation rates; 3D acellular scaffolds with autologous endometrial cells demonstrate potential in regenerating endometrial tissue in cases unresponsive to conventional therapies | Highlights innovative approaches combining intrauterine therapies with tissue engineering for endometrial regeneration | Fertility and Reproduction |
Esfandiari F, et al. (2021) [62] | EnO | Endometrial diseases | Identified DNA methylation patterns in HOX genes and their cofactors specific to endometriosis | Provides insights into epigenetic regulation in endometriosis, advancing understanding of the disease at the molecular level | Fertil Steril |
Esfandiari F, et al. (2021) [63] | EnO | Endometrial diseases | Found that progesterone signaling was disturbed in a preclinical model of advanced endometriosis | Provides valuable insights into the hormonal dysregulation in endometriosis, advancing therapeutic targets for treatment | Reprod Biomed Online |
Bui BN, et al. (2020) [64] | EO | Endometrial diseases | Demonstrated the successful establishment of organoids from cryopreserved endometrial tissue of infertile women, showing organoid culture feasibility | Provides a reliable model for fertility research and endometrial disease studies | Reprod Biomed Online |
Bui BN, et al. (2024) [67] | EO | Infertility | Enrichment of cell cycle pathways in organoids compared to fertile women | Advances understanding of progesterone treatment in fertility | J Assist Reprod Genet |
Hibaoui Y, et al. (2020) [73] | EO | Endometrial development and disease | Discussed the creation of organoid models to study endometrial development and diseases, focusing on their potential applications in understanding endometrial pathology | Provides valuable insight into the potential of organoid models in studying endometrial diseases | Front Cell Dev Biol |
Chen X, et al. (2023) [74] | PDOs | Endometrial cancer, therapeutic target identification | Identified an ASO targeting SNORD14E for endometrial cancer, reducing FOXM1 expression and β-catenin nuclear accumulation. | Contributes to the development of new therapeutic strategies for endometrial cancer | J Exp Clin Cancer Res |
Chen J, et al. (2023) [75] | MDOs | Endometrial cancer, genetic drivers, cancer model | Developed a new model for endometrial cancer in mice, revealing the roles of genetic drivers and their treatment susceptibilities | Provides insights into the genetic underpinnings of endometrial cancer and aids in the development of targeted therapies | Adv Sci (Weinh) |
Maru Y, et al. (2019) [76] | PDOs | Gynecologic tumors, preclinical model | Efficient use of PDOs as models for gynecologic tumors, allowing for accurate replication of patient cancer characteristics and treatment testing | Provides a platform for personalized treatment strategies, enhancing understanding of gynecologic cancer biology | Gynecol Oncol |
Sengal AT, et al. (2023) [77] | PDXOs | Endometrial cancer, FGFR2c isoform expression, drug sensitivity | PDXOs with FGFR2c isoform expression are sensitive to FGFR inhibition, indicating the potential for targeted therapies. | Demonstrates the use of organoids for personalized medicine and preclinical drug testing in endometrial cancer. | NPJ Precis Oncol |
Bi J, et al. (2021) [78] | GC-PDOs | Gynecologic cancer modeling and drug sensitivity testing | Successfully cultured patient-derived organoids from gynecologic cancers for disease modeling and drug sensitivity testing. | Supports the development of personalized treatment approaches for gynecologic cancers. | Cancers (Basel) |
Girda E, et al. (2017) [79] | EC-PDOs | Exploring drug sensitivity testing | Demonstrated feasibility of using organoids for drug sensitivity testing | Enables personalized cancer treatment approaches | Int J Gynecol Cancer |
Bishop RC, et al. (2020) [81] | Murine EO | Modeling Chlamydia infection in the endometrium | Successfully used murine endometrial organoids to study Chlamydia infection dynamics | Provides a valuable model for investigating reproductive tract infections and potential treatments | Front Cell Infect Microbiol |
Dolat L, et al. (2021) [82] | EO | Interactions between Chlamydia and epithelial/immune cells | Successfully models Chlamydia interactions with epithelial and immune cells in the endometrium | Provides a new model for studying immune responses and bacterial infections in the reproductive tract | J Cell Sc |
Abady MM, et al. (2024) [83] | HO | Drug toxicity | Organoid models can be used to assess the reproductive toxicity of neurogenic/neuroprotective drugs, an alternative to animal models | Provides evidence that organoid models can offer more accurate insights into drug toxicity, particularly for reproductive safety | Front Pharmacol |
Rawlings TM, et al. (2021) [90] | EO | Endometrial implantation | Focused on using organoids to model endometrial implantation processes and other related functions | Highlights the potential of organoid models in studying endometrial biology and improving reproductive health therapies | Reproduction and Fertility |
Kleinová M, et al. (2024) [91] | EO | Generation, implantation modeling, and clinical perspectives | Explores the potential of endometrial organoids and assembloids for studying reproduction, including modeling implantation processes | Provides insight into the future clinical applications of organoid models in reproductive health | Front Cell Dev Biol |
Gatimel N, et al. (2024) [92] | HFTOs | Sperm motility and organoid environment | Demonstrates that human fallopian tube organoids support sperm motility, which could enhance understanding of fertility and reproduction | Highlights the potential of organoid models to mimic reproductive tract conditions and provide a better understanding of fertility | Human Reproduction |
Barry F, et al. (2024) [93] | TO | Embryo implantation and pregnancy | Developed trophoblast organoids to study the effects of oxygen concentration on preimplantation embryo culture, offering insights into the early stages of pregnancy | Provides a novel 3D model to explore trophoblast function and the impact of oxygen levels on embryo development, which is crucial for improving in vitro fertilization techniques | Human Reproduction |
Van den Berg J, et al. (2024) [98] | EO | Endometrial receptivity | Seminal plasma exposure altered the transcriptomic profile of endometrial organoids, revealing differences based on fertility status | Provides insight into how seminal plasma may modulate endometrial receptivity and fertility, using a physiologically relevant organoid model | Human Reproduction |
Deane JA, et al. (2017) [100] | EO | Endometrial research and personalized medicine | The study highlights the potential of endometrial organoids as in vitro models for studying endometrial diseases and personalized medicine. | Demonstrates the utility of endometrial organoids for disease modeling and patient-specific drug testing. | Biol Reprod |
Gu ZY, et al. (2020) [101] | EO | Endometrial diseases | This study introduces endometrial organoids as a novel model for investigating endometrial diseases, providing insights into disease mechanisms and potential therapeutic strategies | Supports the potential of endometrial organoids as a reliable in vitro model for advancing research and treatment strategies for endometrial diseases | Biol Reprod |
Fitzgerald HC, et al. (2019) [102] | EO | Self-renewing endometrial epithelial organoids in human uterine research | The study demonstrates the successful establishment of self-renewing endometrial epithelial organoids from the human uterus, which can be used to investigate endometrial biology and disease mechanisms | Highlights the potential of human endometrial organoids in advancing the understanding of endometrial diseases and in personalized medicine | PNAS |
Cochrane DR, et al. (2020) [104] | EO | Cell type biomarkers | Identified novel cell type markers and cryptic differentiation patterns in primary tumors using normal endometrial-derived organoids | Enhances understanding of cellular heterogeneity in endometrial tissues and can aid in better characterization of endometrial cancers | J Pathol |
Luddi A, et al. (2020) [105] | EO | Endometrium-embryo cross-talk at the implantation site | Human endometrial organoids model the interactions between the endometrium and embryo at the implantation site | Provides a novel in vitro tool for studying implantation processes in fertility research | Cells |
Giobbe GG, et al. (2019) [106] | EndodO | Organoid development | Demonstrated that tissue-specific ECM hydrogels can support long-term growth and maintenance of endodermal organoids | Offers a biocompatible, physiologically relevant scaffold to improve organoid culture fidelity | Nature Communications |
Murphy AR, et al. (2019) [107] | EO | Organoid development | Successfully established and visualized a reproducible method for creating endometrial organoids that include both epithelial and stromal components | Provides a reliable and accessible model for studying human endometrial physiology and pathophysiology | Journal of Visualized Experiments |
Abbas Y, et al. (2020) [108] | EO | Organoid development | Successfully generated a multicellular human endometrial model incorporating stromal and epithelial cells, recapitulating structural and functional features | Enhances the ability to study implantation, regeneration, and menstrual cycle processes in vitro | Interface Focus |
Simintiras CA, et al. (2021) [109] | EO | Organoid development | Identified and profiled metabolites secreted by endometrial organoids, revealing active metabolic signaling relevant to implantation and endometrial function | Offers insights into endometrial physiology and potential biomarkers for reproductive health | PNAS |
Co JY, et al. (2021) [110] | GIO | Organoid development | Demonstrated a method to control organoid polarity, enabling luminal access and better modeling of host–pathogen interactions | Facilitates advanced studies of gastrointestinal infections and epithelial function in a physiologically relevant model | Nature Protocols |
Li JL, et al. (2022) [111] | EO | Organoid development | Developed endometrial organoids to model key features of the human endometrium, useful for understanding menstrual cycle dynamics and related disorders | Provides a powerful model for studying endometrial biology and endometrial-related diseases in vitro | Reproductive and Developmental Medicine |
Esfandiari F, et al., (2022) [112] | EnO | Prospects and challenges of using endometriosis organoids | Discussed the potential applications and challenges of generating endometriosis organoids for studying the disease and testing treatments | Highlights the promise of organoids in advancing research on endometriosis, while also addressing technical challenges in their use for therapeutic development | Reprod Biomed Online |
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Jabri, A.; Alsharif, M.; Abbad, T.; Taftafa, B.; Mhannayeh, A.; Elsalti, A.; Attia, F.; Mir, T.A.; Saadeldin, I.; Yaqinuddin, A. Endometrial Organoids and Their Role in Modeling Human Infertility. Cells 2025, 14, 829. https://doi.org/10.3390/cells14110829
Jabri A, Alsharif M, Abbad T, Taftafa B, Mhannayeh A, Elsalti A, Attia F, Mir TA, Saadeldin I, Yaqinuddin A. Endometrial Organoids and Their Role in Modeling Human Infertility. Cells. 2025; 14(11):829. https://doi.org/10.3390/cells14110829
Chicago/Turabian StyleJabri, Abdullah, Mohamed Alsharif, Tasnim Abbad, Bader Taftafa, Abdulaziz Mhannayeh, Abdulrahman Elsalti, Fayrouz Attia, Tanveer Ahmad Mir, Islam Saadeldin, and Ahmed Yaqinuddin. 2025. "Endometrial Organoids and Their Role in Modeling Human Infertility" Cells 14, no. 11: 829. https://doi.org/10.3390/cells14110829
APA StyleJabri, A., Alsharif, M., Abbad, T., Taftafa, B., Mhannayeh, A., Elsalti, A., Attia, F., Mir, T. A., Saadeldin, I., & Yaqinuddin, A. (2025). Endometrial Organoids and Their Role in Modeling Human Infertility. Cells, 14(11), 829. https://doi.org/10.3390/cells14110829