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.

  • Review Article
  • Published:

Clinical applications of human organoids

Abstract

Organoids are innovative three-dimensional and self-organizing cell cultures of various lineages that can be used to study diverse tissues and organs. Human organoids have dramatically increased our understanding of developmental and disease biology. They provide a patient-specific model to study known diseases, with advantages over animal models, and can also provide insights into emerging and future health threats related to climate change, zoonotic infections, environmental pollutants or even microgravity during space exploration. Furthermore, organoids show potential for regenerative cell therapies and organ transplantation. Still, several challenges for broad clinical application remain, including inefficiencies in initiation and expansion, increasing model complexity and difficulties with upscaling clinical-grade cultures and developing more organ-specific human tissue microenvironments. To achieve the full potential of organoid technology, interdisciplinary efforts are needed, integrating advances from biology, bioengineering, computational science, ethics and clinical research. In this Review, we showcase pivotal achievements in epithelial organoid research and technologies and provide an outlook for the future of organoids in advancing human health and medicine.

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

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The ripple effect of the epithelial organoid discovery.
Fig. 2: Technological advances with organoids.
Fig. 3: Organoid-based precision medicine and clinical decision making.
Fig. 4: Organoid-based assessment of the exposome and environmental risk factors.

Similar content being viewed by others

References

  1. Eiraku, M. et al. Self-organized formation of polarized cortical tissues from ESCs and its active manipulation by extrinsic signals. Cell Stem Cell 3, 519–532 (2008).

    CAS  Google Scholar 

  2. Marsee, A. et al. Building consensus on definition and nomenclature of hepatic, pancreatic, and biliary organoids. Cell Stem Cell 28, 816–832 (2021).

    CAS  Google Scholar 

  3. Sato, T. et al. Single Lgr5 stem cells build crypt–villus structures in vitro without a mesenchymal niche. Nature 459, 262–265 (2009).

    CAS  PubMed  Google Scholar 

  4. Spence, J. R. et al. Directed differentiation of human pluripotent stem cells into intestinal tissue in vitro. Nature 470, 105–109 (2011).

    PubMed  Google Scholar 

  5. Jiang, S. et al. Macrophage–organoid co-culture model for identifying treatment strategies against macrophage-related gemcitabine resistance. J. Exp. Clin. Cancer Res. 42, 199 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Zhou, G. et al. Modelling immune cytotoxicity for cholangiocarcinoma with tumour-derived organoids and effector T cells. Br. J. Cancer 127, 649–660 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Liu, J. et al. Cancer-associated fibroblasts provide a stromal niche for liver cancer organoids that confers trophic effects and therapy resistance. Cell. Mol. Gastroenterol. Hepatol. 11, 407–431 (2021).

    PubMed  Google Scholar 

  8. Willemse, J., van der Laan, L. J. W., de Jonge, J. & Verstegen, M. M. A. Design by nature: emerging applications of native liver extracellular matrix for cholangiocyte organoid-based regenerative medicine. Bioengineering 9, 110 (2022).

    PubMed  PubMed Central  Google Scholar 

  9. van Tienderen, G. S. et al. Extracellular matrix drives tumor organoids toward desmoplastic matrix deposition and mesenchymal transition. Acta Biomater. 158, 115–131 (2023).

    PubMed  Google Scholar 

  10. Ingber, D. E. Human organs-on-chips for disease modelling, drug development and personalized medicine. Nat. Rev. Genet. 23, 467–491 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Matai, I., Kaur, G., Seyedsalehi, A., McClinton, A. & Laurencin, C. T. Progress in 3D bioprinting technology for tissue/organ regenerative engineering. Biomaterials 226, 119536 (2020).

    CAS  PubMed  Google Scholar 

  12. Hendriks, D. et al. Engineered human hepatocyte organoids enable CRISPR-based target discovery and drug screening for steatosis. Nat. Biotechnol. 41, 1567–1581 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Hendriks, D., Artegiani, B., Hu, H., Chuva de Sousa Lopes, S. & Clevers, H. Establishment of human fetal hepatocyte organoids and CRISPR–Cas9-based gene knockin and knockout in organoid cultures from human liver. Nat. Protoc. 16, 182–217 (2021).

    CAS  PubMed  Google Scholar 

  14. Sampaziotis, F. et al. Cholangiocyte organoids can repair bile ducts after transplantation in the human liver. Science 371, 839–846 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Ahn, S. J. Standards for organoids. Int. J. Stem Cells 17, 99–101 (2024).

    Google Scholar 

  16. Ahn, S. J. et al. Essential guidelines for manufacturing and application of organoids. Int. J. Stem Cells 17, 102–112 (2024).

    Google Scholar 

  17. Kelley, K. W. & Pașca, S. P. Human brain organogenesis: toward a cellular understanding of development and disease. Cell 185, 42–61 (2022).

    CAS  PubMed  Google Scholar 

  18. Bombieri, C. et al. Advanced cellular models for rare disease study: exploring neural, muscle and skeletal organoids. Int. J. Mol. Sci. 25, 1014 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Okumuş, E. B., Böke, Ö. B., Turhan, S. & Doğan, A. From development to future prospects: the adipose tissue & adipose tissue organoids. Life Sci. 351, 122758 (2024).

    Google Scholar 

  20. Wang, X. H., Liu, N., Zhang, H., Yin, Z. S. & Zha, Z. G. From cells to organs: progress and potential in cartilaginous organoids research. J. Transl. Med. 21, 926 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Neal, J. T. et al. Organoid modeling of the tumor immune microenvironment. Cell 175, 1972–1988 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Schuth, S. et al. Patient-specific modeling of stroma-mediated chemoresistance of pancreatic cancer using a three-dimensional organoid–fibroblast co-culture system. J. Exp. Clin. Cancer Res. 41, 312 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Strating, E. et al. Co-cultures of colon cancer cells and cancer-associated fibroblasts recapitulate the aggressive features of mesenchymal-like colon cancer. Front. Immunol. 14, 1053920 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Homan, K. A. et al. Flow-enhanced vascularization and maturation of kidney organoids in vitro. Nat. Methods 16, 255–262 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Willemse, J. et al. Scaffolds obtained from decellularized human extrahepatic bile ducts support organoids to establish functional biliary tissue in a dish. Biotechnol. Bioeng. 118, 836–851 (2021).

  26. Rüland, L. et al. Organoid models of fibrolamellar carcinoma mutations reveal hepatocyte transdifferentiation through cooperative BAP1 and PRKAR2A loss. Nat. Commun. 14, 2377 (2023).

    PubMed  PubMed Central  Google Scholar 

  27. Lawlor, K. T. et al. Cellular extrusion bioprinting improves kidney organoid reproducibility and conformation. Nat. Mater. 20, 260–271 (2021).

    CAS  PubMed  Google Scholar 

  28. Bernal, P. N. et al. Volumetric bioprinting of organoids and optically tuned hydrogels to build liver-like metabolic biofactories. Adv. Mater. 34, e2110054 (2022).

    PubMed  Google Scholar 

  29. Wang, X., Luo, Y., Ma, Y., Wang, P. & Yao, R. Converging bioprinting and organoids to better recapitulate the tumor microenvironment. Trends Biotechnol. 42, 648–663 (2024).

  30. Chen, H. et al. Acoustic bioprinting of patient-derived organoids for predicting cancer therapy responses. Adv. Healthc. Mater. 11, e2102784 (2022).

    PubMed  Google Scholar 

  31. Brassard, J. A., Nikolaev, M., Hübscher, T., Hofer, M. & Lutolf, M. P. Recapitulating macro-scale tissue self-organization through organoid bioprinting. Nat. Mater. 20, 22–29 (2021).

    CAS  PubMed  Google Scholar 

  32. Urciuolo, A. et al. Hydrogel-in-hydrogel live bioprinting for guidance and control of organoids and organotypic cultures. Nat. Commun. 14, 3128 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Yarali, E. et al. 4D printing for biomedical applications. Adv. Mater. 36, e2402301 (2024).

    PubMed  Google Scholar 

  34. Chen, A. et al. Multimaterial 3D and 4D bioprinting of heterogenous constructs for tissue engineering. Adv. Mater. 36, e2307686 (2023).

    PubMed  Google Scholar 

  35. Chadwick, M. et al. Rapid processing and drug evaluation in glioblastoma patient-derived organoid models with 4D bioprinted arrays. iScience 23, 101365 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Schuster, B. et al. Automated microfluidic platform for dynamic and combinatorial drug screening of tumor organoids. Nat. Commun. 11, 5271 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Shi, H. et al. Organoid intelligence: integration of organoid technology and artificial intelligence in the new era of in vitro models. Med. Nov. Technol. Devices 21, 100276 (2024).

    PubMed  Google Scholar 

  38. Bai, L. et al. AI-enabled organoids: construction, analysis, and application. Bioact. Mater. 31, 525–548 (2024).

    PubMed  Google Scholar 

  39. Du, X. et al. Organoids revealed: morphological analysis of the profound next generation in-vitro model with artificial intelligence. Biodes. Manuf. 6, 319–339 (2023).

    Google Scholar 

  40. Fujii, M. & Sato, T. Somatic cell-derived organoids as prototypes of human epithelial tissues and diseases. Nat. Mater. 20, 156–169 (2021).

    CAS  PubMed  Google Scholar 

  41. Viergever, B. J. et al. Urine-derived bladder cancer organoids (urinoids) as a tool for cancer longitudinal response monitoring and therapy adaptation. Br. J. Cancer 130, 369–379 (2024).

    CAS  PubMed  Google Scholar 

  42. Sun, G. et al. Formation and optimization of three-dimensional organoids generated from urine-derived stem cells for renal function in vitro. Stem Cell Res. Ther. 11, 309 (2020).

    CAS  Google Scholar 

  43. Soroka, C. J. et al. Bile-derived organoids from patients with primary sclerosing cholangitis recapitulate their inflammatory immune profile. Hepatology 70, 871–882 (2019).

    CAS  PubMed  Google Scholar 

  44. Roos, F. J. M. et al. Human bile contains cholangiocyte organoid-initiating cells which expand as functional cholangiocytes in non-canonical Wnt stimulating conditions. Front. Cell Dev. Biol. 8, 630492 (2021).

    Google Scholar 

  45. Gerli, M. F. M. et al. Single-cell guided prenatal derivation of primary fetal epithelial organoids from human amniotic and tracheal fluids. Nat. Med. 30, 875–887 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. van de Wetering, M. et al. Prospective derivation of a living organoid biobank of colorectal cancer patients. Cell 161, 933–945 (2015).

    PubMed  PubMed Central  Google Scholar 

  47. Fujii, M. et al. A colorectal tumor organoid library demonstrates progressive loss of niche factor requirements during tumorigenesis. Cell Stem Cell 18, 827–838 (2016).

    CAS  Google Scholar 

  48. Gao, D. et al. Organoid cultures derived from patients with advanced prostate cancer. Cell 159, 176–187 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Boj, S. F. et al. Organoid models of human and mouse ductal pancreatic cancer. Cell 160, 324–338 (2015).

    CAS  PubMed  Google Scholar 

  50. Nanki, K. et al. Somatic inflammatory gene mutations in human ulcerative colitis epithelium. Nature 577, 254–259 (2020).

    CAS  PubMed  Google Scholar 

  51. Nanki, K. et al. Divergent routes toward Wnt and R-spondin niche independency during human gastric carcinogenesis. Cell 174, 856–869 (2018).

    CAS  PubMed  Google Scholar 

  52. Broutier, L. et al. Human primary liver cancer-derived organoid cultures for disease modeling and drug screening. Nat. Med. 12, 1424–1435 (2017).

    Google Scholar 

  53. Saito, Y. et al. Establishment of patient-derived organoids and drug screening for biliary tract carcinoma. Cell Rep. 27, 1265–1276 (2019).

    CAS  PubMed  Google Scholar 

  54. Sachs, N. et al. A living biobank of breast cancer organoids captures disease heterogeneity. Cell 172, 373–386 (2018).

    CAS  PubMed  Google Scholar 

  55. Kawasaki, K. et al. An organoid biobank of neuroendocrine neoplasms enables genotype–phenotype mapping. Cell 183, 1420–1435 (2020).

    CAS  PubMed  Google Scholar 

  56. Pauli, C. et al. Personalized in vitro and in vivo cancer models to guide precision medicine. Cancer Discov. 7, 462–477 (2017).

    PubMed  PubMed Central  Google Scholar 

  57. Tiriac, H. et al. Organoid profiling identifies common responders to chemotherapy in pancreatic cancer. Cancer Discov. 8, 1112–1129 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. van Tienderen, G. S. et al. Hepatobiliary tumor organoids for personalized medicine: a multicenter view on establishment, limitations, and future directions. Cancer Cell 40, 226–230 (2022).

    PubMed  Google Scholar 

  59. Seino, T. et al. Human pancreatic tumor organoids reveal loss of stem cell niche factor dependence during disease progression. Cell Stem Cell 22, 454–467 (2018).

    CAS  Google Scholar 

  60. Abaza, A. et al. Programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) immunotherapy: a promising breakthrough in cancer therapeutics. Cureus 15, e44582 (2023).

    PubMed  PubMed Central  Google Scholar 

  61. Shiravand, Y. et al. Immune checkpoint inhibitors in cancer therapy. Curr. Oncol. 29, 3044–3060 (2022).

    PubMed  PubMed Central  Google Scholar 

  62. Sharma, P. et al. Immune checkpoint therapy—current perspectives and future directions. Cell 186, 1652–1669 (2023).

    CAS  PubMed  Google Scholar 

  63. Sharma, P. & Allison, J. P. Dissecting the mechanisms of immune checkpoint therapy. Nat. Rev. Immunol. 20, 75–76 (2020).

    CAS  PubMed  Google Scholar 

  64. Sleeboom, J. J. F. et al. The extracellular matrix as hallmark of cancer and metastasis: from biomechanics to therapeutic targets. Sci. Transl. Med. 16, eadg3840 (2024).

    CAS  PubMed  Google Scholar 

  65. Dijkstra, K. K. et al. Generation of tumor-reactive T cells by co-culture of peripheral blood lymphocytes and tumor organoids. Cell 174, 1586–1598 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Magré, L. et al. Emerging organoid–immune co-culture models for cancer research: from oncoimmunology to personalized immunotherapies. J. Immunother. Cancer 11, e006290 (2023).

    PubMed  PubMed Central  Google Scholar 

  67. van Tienderen, G., Groot Koerkamp, B., IJzermans, J., van der Laan, L. & Verstegen, M. Recreating tumour complexity in a dish: organoid models to study liver cancer cells and their extracellular environment. Cancers 11, 1706 (2019).

    PubMed  PubMed Central  Google Scholar 

  68. van Tienderen, G. S. et al. Modelling metastatic colonization of cholangiocarcinoma organoids in decellularized lung and lymph nodes. Front. Oncol. 12, 1101901 (2022).

    PubMed  Google Scholar 

  69. Polak, R., Zhang, E. T. & Kuo, C. J. Cancer organoids 2.0: modelling the complexity of the tumour immune microenvironment. Nat. Rev. Cancer 24, 523–539 (2024).

    CAS  PubMed  Google Scholar 

  70. LeSavage, B. L., Suhar, R. A., Broguiere, N., Lutolf, M. P. & Heilshorn, S. C. Next-generation cancer organoids. Nat. Mater. 21, 143–159 (2022).

    CAS  PubMed  Google Scholar 

  71. Rosendahl Huber, A. et al. Improved detection of colibactin-induced mutations by genotoxic E. coli in organoids and colorectal cancer. Cancer Cell 42, 487–496 (2024).

    CAS  PubMed  Google Scholar 

  72. Kwong, J. et al. Inflammatory cytokine tumor necrosis factor α confers precancerous phenotype in an organoid model of normal human ovarian surface epithelial cells. Neoplasia 11, 529–541 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Kopper, O. et al. An organoid platform for ovarian cancer captures intra- and interpatient heterogeneity. Nat. Med. 25, 838–849 (2019).

    CAS  PubMed  Google Scholar 

  74. Kessler, M. et al. The Notch and Wnt pathways regulate stemness and differentiation in human fallopian tube organoids. Nat. Commun. 6, 8989 (2015).

    CAS  PubMed  Google Scholar 

  75. Hoffmann, K. et al. Stable expansion of high-grade serous ovarian cancer organoids requires a low-Wnt environment. EMBO J. 39, e104013 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 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 

  78. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Chumduri, C. et al. Opposing Wnt signals regulate cervical squamocolumnar homeostasis and emergence of metaplasia. Nat. Cell Biol. 23, 184–197 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Lõhmussaar, K. et al. Patient-derived organoids model cervical tissue dynamics and viral oncogenesis in cervical cancer. Cell Stem Cell 28, 1380–1396 (2021).

    Google Scholar 

  81. Maru, Y. et al. Establishment and molecular phenotyping of organoids from the squamocolumnar junction region of the uterine cervix. Cancers 12, 694 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Turco, M. Y. et al. Trophoblast organoids as a model for maternal–fetal interactions during human placentation. Nature 564, 263–267 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Haider, S. et al. Self-renewing trophoblast organoids recapitulate the developmental program of the early human placenta. Stem Cell Reports 11, 537–551 (2018).

    CAS  Google Scholar 

  84. 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).

    Google Scholar 

  85. Karthaus, W. R. et al. Identification of multipotent luminal progenitor cells in human prostate organoid cultures. Cell 159, 163–175 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Baert, Y. et al. Primary human testicular cells self-organize into organoids with testicular properties. Stem Cell Reports 8, 30–38 (2017).

    CAS  Google Scholar 

  87. Beshiri, M., Agarwal, S., Yin, J. J. & Kelly, K. Prostate organoids: emerging experimental tools for translational research. J. Clin. Invest. 133, e169616 (2023).

    PubMed  PubMed Central  Google Scholar 

  88. Calà, G., Sina, B., De Coppi, P., Giobbe, G. G. & Gerli, M. F. M. Primary human organoids models: current progress and key milestones. Front. Bioeng. Biotechnol. 11, 1058970 (2023).

    PubMed  PubMed Central  Google Scholar 

  89. Bianchi, D. W. From prenatal genomic diagnosis to fetal personalized medicine: progress and challenges. Nat. Med. 18, 1041–1051 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. de Coppi, P. et al. Regenerative medicine: prenatal approaches. Lancet Child Adolesc. Health 6, 643–653 (2022).

    PubMed  PubMed Central  Google Scholar 

  91. Deprest, J. A. et al. Randomized trial of fetal surgery for moderate left diaphragmatic hernia. N. Engl. J. Med. 385, 119–129 (2021).

    PubMed  PubMed Central  Google Scholar 

  92. Deprest, J. A. et al. Randomized trial of fetal surgery for severe left diaphragmatic hernia. N. Engl. J. Med. 385, 107–118 (2021).

    PubMed  PubMed Central  Google Scholar 

  93. Zani, A. et al. Congenital diaphragmatic hernia. Nat. Rev. Dis. Primers 8, 37 (2022).

    PubMed  Google Scholar 

  94. Cheng, P. P. et al. PM2.5 exposure-induced senescence-associated secretory phenotype in airway smooth muscle cells contributes to airway remodeling. Environ. Pollut. 347, 123674 (2024).

    CAS  PubMed  Google Scholar 

  95. Winkler, A. S. et al. Human airway organoids and microplastic fibers: a new exposure model for emerging contaminants. Environ. Int. 163, 107200 (2022).

    CAS  PubMed  Google Scholar 

  96. Zhou, Y. et al. Low-dose of polystyrene microplastics induce cardiotoxicity in mice and human-originated cardiac organoids. Environ. Int. 179, 108171 (2023).

    CAS  PubMed  Google Scholar 

  97. Cheng, W. et al. Polystyrene microplastics induce hepatotoxicity and disrupt lipid metabolism in the liver organoids. Sci. Total Environ. 806, 150328 (2022).

    CAS  PubMed  Google Scholar 

  98. Astashkina, A. I. et al. Nanoparticle toxicity assessment using an in vitro 3-D kidney organoid culture model. Biomaterials 35, 6323–6331 (2014).

    CAS  PubMed  Google Scholar 

  99. Williams, K. E. et al. Quantitative proteomic analyses of mammary organoids reveals distinct signatures after exposure to environmental chemicals. Proc. Natl Acad. Sci. USA 113, E1343–E1351 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Shaoyong, W. et al. Benzo [a] pyrene-loaded aged polystyrene microplastics promote colonic barrier injury via oxidative stress-mediated Notch signalling. J. Hazard. Mater. 457, 131820 (2023).

    CAS  PubMed  Google Scholar 

  101. Zhang, C. et al. Inhibition of GABAA receptors in intestinal stem cells prevents chemoradiotherapy-induced intestinal toxicity. J. Exp. Med. 219, e20220541 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Cheng, W. et al. The iron matters: aged microplastics disrupted the iron homeostasis in the liver organoids. Sci. Total Environ. 906, 167529 (2024).

    CAS  PubMed  Google Scholar 

  103. Xuan, L. et al. Predictive metabolomic signatures for safety assessment of three plastic nanoparticles using intestinal organoids. Sci. Total Environ. 913, 169606 (2024).

    CAS  PubMed  Google Scholar 

  104. Loiseau, C. & Sorci, G. Can microplastics facilitate the emergence of infectious diseases? Sci. Total Environ. 823, 153694 (2022).

    CAS  PubMed  Google Scholar 

  105. Nii-Trebi, N. I. et al. Dynamics of viral disease outbreaks: a hundred years (1918/19–2019/20) in retrospect — loses, lessons and emerging issues. Rev. Med. Virol. 33, e2475 (2023).

    PubMed  Google Scholar 

  106. Ettayebi, K. et al. Replication of human noroviruses in stem cell-derived human enteroids. Science 353, 1387–1393 (2016).

    PubMed  PubMed Central  Google Scholar 

  107. Garcez, P. P. et al. Zika virus impairs growth in human neurospheres and brain organoids. Science 352, 816–818 (2016).

    CAS  PubMed  Google Scholar 

  108. Karvas, R. M. et al. Stem-cell-derived trophoblast organoids model human placental development and susceptibility to emerging pathogens. Cell Stem Cell 29, 810–825 (2022).

    CAS  Google Scholar 

  109. Wu, H. et al. Zika virus targets human trophoblast stem cells and prevents syncytialization in placental trophoblast organoids. Nat. Commun. 14, 5541 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Lamers, M. M. et al. An organoid-derived bronchioalveolar model for SARS-CoV-2 infection of human alveolar type II-like cells. EMBO J. 40, e105912 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Jansen, J. et al. SARS-CoV-2 infects the human kidney and drives fibrosis in kidney organoids. Cell Stem Cell 29, 217–231 (2022).

    CAS  Google Scholar 

  112. Zhao, B. et al. Recapitulation of SARS-CoV-2 infection and cholangiocyte damage with human liver ductal organoids. Protein Cell 11, 771–775 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Lamers, M. M. et al. SARS-CoV-2 productively infects human gut enterocytes. Science 369, 50–54 (2020).

    CAS  PubMed  Google Scholar 

  114. Li, P. et al. Mpox virus infection and drug treatment modelled in human skin organoids. Nat. Microbiol. 8, 2067–2079 (2023).

    CAS  PubMed  Google Scholar 

  115. Li, P. et al. Mpox virus infects and injures human kidney organoids, but responding to antiviral treatment. Cell Discov. 9, 34 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Merad, M. & Martin, J. C. Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages. Nat. Rev. Immunol. 20, 355–362 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Xu, M. et al. Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen. Nat. Med. 22, 1101–1107 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Han, Y. et al. Identification of SARS-CoV-2 inhibitors using lung and colonic organoids. Nature 589, 270–275 (2021).

    CAS  PubMed  Google Scholar 

  119. Li, P. et al. Recapitulating hepatitis E virus–host interactions and facilitating antiviral drug discovery in human liver-derived organoids. Sci. Adv. 8, eabj5908 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Wagar, L. E. et al. Modeling human adaptive immune responses with tonsil organoids. Nat. Med. 27, 125–135 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Zhou, J. et al. Infection of bat and human intestinal organoids by SARS-CoV-2. Nat. Med. 26, 1077–1083 (2020).

    CAS  PubMed  Google Scholar 

  122. Partridge, L., Deelen, J. & Slagboom, P. E. Facing up to the global challenges of ageing. Nature 561, 45–56 (2018).

    CAS  PubMed  Google Scholar 

  123. López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013).

    PubMed  PubMed Central  Google Scholar 

  124. Blokzijl, F. et al. Tissue-specific mutation accumulation in human adult stem cells during life. Nature 538, 260–264 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Vougioukalaki, M. et al. Different responses to DNA damage determine ageing differences between organs. Aging Cell 21, e13562 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Nguyen, L. et al. Precancerous liver diseases do not cause increased mutagenesis in liver stem cells. Commun. Biol. 4, 1301 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Pentinmikko, N. et al. Notum produced by Paneth cells attenuates regeneration of aged intestinal epithelium. Nature 571, 398–402 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Kobayashi, Y. et al. Persistence of a regeneration-associated, transitional alveolar epithelial cell state in pulmonary fibrosis. Nat. Cell Biol. 22, 934–946 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Nalapareddy, K. et al. Canonical Wnt signaling ameliorates aging of intestinal stem cells. Cell Rep. 18, 2608–2621 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Ferreira-Gonzalez, S. et al. Senolytic treatment preserves biliary regenerative capacity lost through cellular senescence during cold storage. Sci. Transl. Med. 14, eabj4375 (2022).

    CAS  PubMed  Google Scholar 

  131. Krittanawong, C. et al. Human health during space travel: state-of-the-art review. Cells 12, 40 (2022).

    PubMed  PubMed Central  Google Scholar 

  132. Garrett-Bakelman, F. E. et al. The NASA Twins Study: a multidimensional analysis of a year-long human spaceflight. Science 364, eaau8650 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Kirkpatrick, A. W. et al. Do we have the guts to go? The abdominal compartment, intra-abdominal hypertension, the human microbiome and exploration class space missions. Can. J. Surg. 63, E581–E593 (2020).

    PubMed  PubMed Central  Google Scholar 

  134. Crucian, B. et al. Incidence of clinical symptoms during long-duration orbital spaceflight. Int. J. Gen. Med. 9, 383–391 (2016).

    PubMed  PubMed Central  Google Scholar 

  135. Turroni, S. et al. Gut microbiome and space travelers’ health: state of the art and possible pro/prebiotic strategies for long-term space missions. Front. Physiol. 11, 553929 (2020).

    PubMed  PubMed Central  Google Scholar 

  136. Mercadante, V. et al. Salivary gland hypofunction and/or xerostomia induced by nonsurgical cancer therapies: ISOO/MASCC/ASCO guideline. J. Clin. Oncol. 39, 2825–2843 (2021).

    CAS  PubMed  Google Scholar 

  137. Cinat, D., Coppes, R. P. & Barazzuol, L. DNA damage-induced inflammatory microenvironment and adult stem cell response. Front. Cell Dev. Biol. 9, 729136 (2021).

    PubMed  PubMed Central  Google Scholar 

  138. van Luijk, P. et al. Sparing the region of the salivary gland containing stem cells preserves saliva production after radiotherapy for head and neck cancer. Sci. Transl. Med. 7, 305ra147 (2015).

    PubMed  PubMed Central  Google Scholar 

  139. Maimets, M. et al. Long-term in vitro expansion of salivary gland stem cells driven by Wnt signals. Stem Cell Reports 6, 150–162 (2016).

    CAS  PubMed  Google Scholar 

  140. Pringle, S. et al. Human salivary gland stem cells functionally restore radiation damaged salivary glands. Stem Cells 34, 640–652 (2016).

    CAS  PubMed  Google Scholar 

  141. Zanten, J. V. et al. Optimization of the production process of clinical-grade human salivary gland organoid-derived cell therapy for the treatment of radiation-induced xerostomia in head and neck cancer. Pharmaceutics 16, 435 (2024).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Gutiérrez, E. & Andrés, A. Selection of donor and organ viability criteria: expanding donation criteria. J. Ren. Care 33, 83–88 (2007).

    Google Scholar 

  143. Lascaris, B., de Meijer, V. E. & Porte, R. J. Normothermic liver machine perfusion as a dynamic platform for regenerative purposes: what does the future have in store for us? J. Hepatol. 77, 825–836 (2022).

    PubMed  Google Scholar 

  144. Schurink, I. J., de Jonge, J. & van der Laan, L. J. W. Organoid technology starts to deliver: repairing damaged liver grafts during normothermic machine perfusion. Transplantation 105, 1886–1887 (2021).

    PubMed  Google Scholar 

  145. Levink, I. J. M. et al. Optimization of pancreatic juice collection: a first step toward biomarker discovery and early detection of pancreatic cancer. Am. J. Gastroenterol. 115, 2103–2108 (2020).

    PubMed  Google Scholar 

  146. Guo, H. et al. 3-D human renal tubular organoids generated from urine-derived stem cells for nephrotoxicity screening. ACS Biomater. Sci. Eng. 6, 6701–6709 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Schneeberger, K. et al. Large-scale production of LGR5-positive bipotential human liver stem cells. Hepatology 72, 257–270 (2020).

    CAS  PubMed  Google Scholar 

  148. Madl, C. M., Heilshorn, S. C. & Blau, H. M. Bioengineering strategies to accelerate stem cell therapeutics. Nature 557, 335–342 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Below, C. R. et al. A microenvironment-inspired synthetic three-dimensional model for pancreatic ductal adenocarcinoma organoids. Nat. Mater. 21, 110–119 (2022).

    CAS  PubMed  Google Scholar 

  150. Gnecco, J. S. et al. Organoid co-culture model of the human endometrium in a fully synthetic extracellular matrix enables the study of epithelial–stromal crosstalk. Med 4, 554–579 (2023).

    CAS  PubMed  Google Scholar 

  151. Gjorevski, N. et al. Designer matrices for intestinal stem cell and organoid culture. Nature 539, 560–564 (2016).

    CAS  PubMed  Google Scholar 

  152. Willemse, J. et al. Hydrogels derived from decellularized liver tissue support the growth and differentiation of cholangiocyte organoids. Biomaterials 284, 121473 (2022).

    CAS  PubMed  Google Scholar 

  153. Martinez-Garcia, F. D. et al. Architecture and composition dictate viscoelastic properties of organ-derived extracellular matrix hydrogels. Polymers 13, 3113 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Liguori, G. R. et al. Molecular and biomechanical clues from cardiac tissue decellularized extracellular matrix drive stromal cell plasticity. Front. Bioeng. Biotechnol. 8, 520 (2020).

    PubMed  PubMed Central  Google Scholar 

  155. Elomaa, L., Keshi, E., Sauer, I. M. & Weinhart, M. Development of GelMA/PCL and dECM/PCL resins for 3D printing of acellular in vitro tissue scaffolds by stereolithography. Mater. Sci. Eng. C Mater. Biol. Appl. 112, 110958 (2020).

    CAS  PubMed  Google Scholar 

  156. de Jongh, D., Massey, E. K., consortium, V. & Bunnik, E. M. Organoids: a systematic review of ethical issues. Stem Cell Res. Ther. 13, 337 (2022).

    Google Scholar 

  157. Barnhart, A. J. & Dierickx, K. The many moral matters of organoid models: a systematic review of reasons. Med. Health Care Philos. 25, 545–560 (2022).

    Google Scholar 

  158. Bredenoord, A. L., Clevers, H. & Knoblich, J. A. Human tissues in a dish: the research and ethical implications of organoid technology. Science 355, eaaf9414 (2017).

    PubMed  Google Scholar 

  159. Hyun, I., Scharf-Deering, J. C. & Lunshof, J. E. Ethical issues related to brain organoid research. Brain Res. 1732, 146653 (2020).

    CAS  Google Scholar 

  160. de Graeff, N., De Proost, L. & Munsie, M. ‘Ceci n’est pas un embryon?’ The ethics of human embryo model research. Nat. Methods 20, 1863–1867 (2023).

    PubMed  PubMed Central  Google Scholar 

  161. Jongsma, K. R. & Bredenoord, A. L. Ethics parallel research: an approach for (early) ethical guidance of biomedical innovation. BMC Med. Ethics 21, 81 (2020).

    PubMed  PubMed Central  Google Scholar 

  162. Kramer, K. When is something an alternative? A general account applied to animal-free alternatives to animal research. Camb. Q. Healthc. Ethics 33, 89–101 (2024).

    PubMed  Google Scholar 

  163. Boers, S. N. & Bredenoord, A. L. Consent for governance in the ethical use of organoids. Nat. Cell Biol. 20, 642–645 (2018).

    CAS  PubMed  Google Scholar 

  164. Lensink, M. A. et al. Responsible use of organoids in precision medicine: the need for active participant involvement. Development 147, dev177972 (2020).

    CAS  PubMed  Google Scholar 

  165. Boers, S. N., van Delden, J. J., Clevers, H. & Bredenoord, A. L. Organoid biobanking: identifying the ethics: organoids revive old and raise new ethical challenges for basic research and therapeutic use. EMBO Rep. 17, 938–941 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Seah, C. & Brennand, K. J. Pandemic city: village-in-a-dish unlocks dynamic genetic effects in the brain. Cell Stem Cell 30, 239–241 (2023).

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Monique M. A. Verstegen.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Medicine thanks Karuna Ganesh and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Karen O’Leary, in collaboration with the Nature Medicine team.

Additional information

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

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) 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

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Verstegen, M.M.A., Coppes, R.P., Beghin, A. et al. Clinical applications of human organoids. Nat Med 31, 409–421 (2025). https://doi.org/10.1038/s41591-024-03489-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41591-024-03489-3

This article is cited by

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