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:

Advances in liver and pancreas organoids: how far we have come and where we go next

Nature Reviews Gastroenterology & Hepatology (2025)Cite this article

Subjects

Abstract

Over the past decade, advances in organoid culturing methods have enabled the growth of three-dimensional cellular cultures in vitro with increasing fidelity with respect to the cellular composition, architecture and function of in vivo organs. The increased accessibility and ability to manipulate organoids as an in vitro system have led to a shift in the landscape of experimental biology. Whether derived from stem cells or tissue-resident cells, organoids are now routinely used in studies of development, homeostasis, regeneration and disease modelling, including viral infection and cancer. These applications of organoids are highly relevant for gastrointestinal tissues, including the liver and pancreas. In this Review, we explore the current and emerging advances in liver and pancreas organoid technologies for both discovery and clinical translation research and provide an outlook on the challenges ahead.

Key points

  • Modelling the liver and pancreas using organoid technology provides an accessible, often human-based system for research into fundamental questions regarding their embryonic development, function, disease modelling and clinical applications.

  • Liver and pancreas organoids are generated utilizing multiple sources as starting material, including pluripotent stem cells, embryonic, fetal and adult stem cells, and adult differentiated cells, each with specific advantages and disadvantages.

  • Current liver and pancreas organoid models have enabled a greater understanding of both acquired and inborn diseases that are not possible with in vivo models.

  • Advances in co-culture technologies are leading to the generation of organoids with multiple interacting cell populations found within the in vivo liver or pancreas enabling the production of higher fidelity models with more mature cell types.

  • Standardization of protocols, improvement of organoid architecture accuracy and transition towards chemically defined extracellular matrices will drive advances in the liver and pancreas organoid field.

Access through your institution
Buy or subscribe

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

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Fig. 1: Liver organoids derived from different tissue-resident cells.
Fig. 2: Pancreas organoids derived from different tissue-resident cells.
Fig. 3: Disease modelling using liver organoids.
Fig. 4: Disease modelling using pancreas organoids.

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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  3. Lancaster, M. A. & Huch, M. Disease modelling in human organoids. Dis. Model. Mech. 12, dmm039347 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Treyer, A. & Müsch, A. Hepatocyte polarity. Compr. Physiol. 3, 243–287 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Gissen, P. & Arias, I. M. Structural and functional hepatocyte polarity and liver disease. J. Hepatol. 63, 1023–1037 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Campana, L., Esser, H., Huch, M. & Forbes, S. Liver regeneration and inflammation: from fundamental science to clinical applications. Nat. Rev. Mol. Cell Biol. 22, 608–624 (2021).

    Article  CAS  PubMed  Google Scholar 

  8. Jamieson, J. D. & Palade, G. E. Synthesis, intracellular transport, and discharge of secretory proteins in stimulated pancreatic exocrine cells. J. Cell Biol. 50, 135–158 (1971).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kopp, J. L. et al. Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma. Cancer Cell 22, 737–750 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Logsdon, C. D. & Ji, B. The role of protein synthesis and digestive enzymes in acinar cell injury. Nat. Rev. Gastroenterol. Hepatol. 10, 362–370 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Reichert, M. & Rustgi, A. K. Pancreatic ductal cells in development, regeneration, and neoplasia. J. Clin. Invest. 121, 4572–4578 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Delous, M. et al. Sox9b is a key regulator of pancreaticobiliary ductal system development. PLoS Genet. 8, e1002754 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Gu, G., Dubauskaite, J. & Melton, D. A. Direct evidence for the pancreatic lineage: NGN3+ cells are islet progenitors and are distinct from duct progenitors. Development 129, 2447–2457 (2002).

    Article  CAS  PubMed  Google Scholar 

  14. Romer, A. I. & Sussel, L. Pancreatic islet cell development and regeneration. Curr. Opin. Endocrinol. Diabetes Obes. 22, 255–264 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kisseleva, T. & Brenner, D. A. Hepatic stellate cells and the reversal of fibrosis. J. Gastroenterol. Hepatol. 21, S84–S87 (2006).

    Article  CAS  PubMed  Google Scholar 

  16. Fallowfield, J. A. et al. Scar-associated macrophages are a major source of hepatic matrix metalloproteinase-13 and facilitate the resolution of murine hepatic fibrosis. J. Immunol. 178, 5288–5295 (2007).

    Article  CAS  PubMed  Google Scholar 

  17. Wisse, E., De Zanger, R. B., Charels, K., Van Der Smissen, P. & McCuskey, R. S. The liver sieve: considerations concerning the structure and function of endothelial fenestrae, the sinusoidal wall and the space of Disse. Hepatology 5, 683–692 (1985).

    Article  CAS  PubMed  Google Scholar 

  18. Coelho, I., Duarte, N., Macedo, M. P. & Penha-Gonçalves, C. Insights into macrophage/monocyte-endothelial cell crosstalk in the liver: a role for Trem-2. J. Clin. Med. 10, 1248 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Braet, F. & Wisse, E. Structural and functional aspects of liver sinusoidal endothelial cell fenestrae: a review. Comp. Hepatol. 1, 1 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Tuchweber, B., Desmoulière, A., Bochaton-Piallat, M. L., Rubbia-Brandt, L. & Gabbiani, G. Proliferation and phenotypic modulation of portal fibroblasts in the early stages of cholestatic fibrosis in the rat. Lab. Invest. 74, 265–278 (1996).

    CAS  PubMed  Google Scholar 

  21. Beaussier, M. et al. Prominent contribution of portal mesenchymal cells to liver fibrosis in ischemic and obstructive cholestatic injuries. Lab. Invest. 87, 292–303 (2007).

    Article  CAS  PubMed  Google Scholar 

  22. Mass, E. et al. Specification of tissue-resident macrophages during organogenesis. Science 353, aaf4238 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Nairz, M., Theurl, I., Swirski, F. K. & Weiss, G. ‘Pumping iron’ – how macrophages handle iron at the systemic, microenvironmental, and cellular levels. Pflug. Arch. 469, 397–418 (2017).

    Article  CAS  Google Scholar 

  24. Hwang, R. F. et al. Cancer-associated stromal fibroblasts promote pancreatic tumor progression. Cancer Res. 68, 918–926 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Apte, M. V., Wilson, J. S., Lugea, A. & Pandol, S. J. A starring role for stellate cells in the pancreatic cancer microenvironment. Gastroenterology 144, 1210–1219 (2013).

    Article  PubMed  Google Scholar 

  26. Olsson, R. & Carlsson, P.-O. The pancreatic islet endothelial cell: emerging roles in islet function and disease. Int. J. Biochem. Cell Biol. 38, 710–714 (2006).

    Article  CAS  PubMed  Google Scholar 

  27. Kao, D.-I. et al. Endothelial cells control pancreatic cell fate at defined stages through EGFL7 signaling. Stem Cell Rep. 4, 181–189 (2015).

    Article  CAS  Google Scholar 

  28. Younossi, Z. M. et al. The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review. Hepatology 77, 1335–1347 (2023).

    Article  PubMed  Google Scholar 

  29. Devarbhavi, H. et al. Global Burden of Liver Disease: 2023 update. J. Hepatol. 79, 516–537 (2023).

    Article  PubMed  Google Scholar 

  30. Li, T. et al. Global and regional burden of pancreatitis: epidemiological trends, risk factors, and projections to 2050 from the Global Burden of Disease Study 2021. BMC Gastroenterol. 24, 398 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  31. Li, X., Zhang, Y., Yan, Z., Jiang, W. & Rui, S. Global, regional and national burden of pancreatic cancer and its attributable risk factors from 2019 to 2021, with projection to 2044. Front. Oncol. 14, 1521788 (2024).

    Article  PubMed  Google Scholar 

  32. NCD Risk Factor Collaboration (NCD-RisC) Worldwide trends in diabetes prevalence and treatment from 1990 to 2022: a pooled analysis of 1108 population-representative studies with 141 million participants. Lancet 404, 2077–2093 (2024).

    Article  Google Scholar 

  33. Prior, N., Inacio, P. & Huch, M. Liver organoids: from basic research to therapeutic applications. Gut 68, 2228–2237 (2019).

    Article  CAS  PubMed  Google Scholar 

  34. Zhao, Z. et al. Organoids. Nat. Rev. Methods Primers 2, 94 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Afonso, M. B., Marques, V., van Mil, S. W. C. & Rodrigues, C. M. P. Human liver organoids: from generation to applications. Hepatology 79, 1432–1451 (2024).

    Article  PubMed  Google Scholar 

  36. Liu, S. et al. Liver organoids: updates on generation strategies and biomedical applications. Stem Cell Res. Ther. 15, 244 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Hu, Y. et al. Liver organoid culture methods. Cell Biosci. 13, 197 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Takebe, T. et al. Vascularized and functional human liver from an iPSC-derived organ bud transplant. Nature 499, 481–484 (2013).

    Article  CAS  PubMed  Google Scholar 

  39. Takebe, T. et al. Massive and reproducible production of liver buds entirely from human pluripotent stem cells. Cell Rep. 21, 2661–2670 (2017).

    Article  CAS  PubMed  Google Scholar 

  40. Sekine, K. et al. Generation of human induced pluripotent stem cell-derived liver buds with chemically defined and animal origin-free media. Sci. Rep. 10, 17937 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ogawa, S. et al. Directed differentiation of cholangiocytes from human pluripotent stem cells. Nat. Biotechnol. 33, 853 (2015).

    Article  CAS  PubMed  Google Scholar 

  42. Sampaziotis, F. et al. Cholangiocytes derived from human induced pluripotent stem cells for disease modeling and drug validation. Nat. Biotechnol. 33, 845 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Godoy, P. et al. Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME. Archives of Toxicol. 87, 1315–1530 (2013).

    Article  CAS  Google Scholar 

  44. Wang, S. et al. Human ESC-derived expandable hepatic organoids enable therapeutic liver repopulation and pathophysiological modeling of alcoholic liver injury. Cell Res. 29, 1009–1026 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Saiki, N. et al. Self-organization of sinusoidal vessels in pluripotent stem cell-derived human liver bud organoids. Nat. Biomed. Eng. https://doi.org/10.1038/s41551-025-01416-6 (2025).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Pagliuca, F. W. et al. Generation of functional human pancreatic β cells in vitro. Cell 159, 428–439 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Rezania, A. et al. Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells. Nat. Biotechnol. 32, 1121–1133 (2014).

    Article  CAS  PubMed  Google Scholar 

  48. Russ, H. A. et al. Controlled induction of human pancreatic progenitors produces functional beta-like cells in vitro. EMBO J. 34, 1759–1772 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Gonçalves, C. A. et al. A 3D system to model human pancreas development and its reference single-cell transcriptome atlas identify signaling pathways required for progenitor expansion. Nat. Commun. 12, 3144 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Huang, L. et al. Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell- and patient-derived tumor organoids. Nat. Med. 21, 1364–1371 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Breunig, M. et al. Modeling plasticity and dysplasia of pancreatic ductal organoids derived from human pluripotent stem cells. Cell Stem Cell 28, 1105–1124.e19 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Wiedenmann, S. et al. Single-cell-resolved differentiation of human induced pluripotent stem cells into pancreatic duct-like organoids on a microwell chip. Nat. Biomed. Eng. 5, 897–913 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Huang, L. et al. Commitment and oncogene-induced plasticity of human stem cell-derived pancreatic acinar and ductal organoids. Cell Stem Cell 28, 1090–1104.e6 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Darrigrand, J. F., Isaacson, A. & Spagnoli, F. M. Generation of human iPSC-derived pancreatic organoids to study pancreas development and disease. F1000Research 14, 575 (2025).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Desai, R., Huang, L., Gonzalez, R. S. & Muthuswamy, S. K. Oncogenic GNAS uses PKA-dependent and independent mechanisms to induce cell proliferation in human pancreatic ductal and acinar organoids. Mol. Cancer Res. 22, 440–451 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Godoy, P. et al. Gene networks and transcription factor motifs defining the differentiation of stem cells into hepatocyte-like cells. J. Hepatol. 63, 934–942 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Hayflick, L. The limited in vitro lifetime of human diploid cell strains. Exp. Cell Res. 37, 614–636 (1965).

    Article  CAS  PubMed  Google Scholar 

  58. Hayflick, L. & Moorhead, P. S. The serial cultivation of human diploid cell strains. Exp. Cell Res. 25, 585–621 (1961).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Huch, M. et al. In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration. Nature 494, 247–250 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Huch, M. et al. Unlimited in vitro expansion of adult bi-potent pancreas progenitors through the Lgr5/R-spondin axis. EMBO J. 32, 2708–2721 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Huch, M. et al. Long-term culture of genome-stable bipotent stem cells from adult human liver. Cell 160, 299–312 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Georgakopoulos, N. et al. Long-term expansion, genomic stability and in vivo safety of adult human pancreas organoids. BMC Dev. Biol. 20, 4 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Aloia, L. et al. Epigenetic remodelling licences adult cholangiocytes for organoid formation and liver regeneration. Nat. Cell Biol. 21, 1321–1333 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Edgar, R. D. et al. Culture-associated DNA methylation changes impact on cellular function of human intestinal organoids. Cell. Mol. Gastroenterol. Hepatol. 14, 1295–1310 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Tapia, N. & Schöler, H. R. Molecular obstacles to clinical translation of iPSCs. Cell Stem Cell 19, 298–309 (2016).

    Article  CAS  PubMed  Google Scholar 

  67. Antoniou, A. et al. Intrahepatic bile ducts develop according to a new mode of tubulogenesis regulated by the transcription factor SOX9. Gastroenterology 136, 2325–2333 (2009).

    Article  PubMed  Google Scholar 

  68. Wesley, B. T. et al. Single-cell atlas of human liver development reveals pathways directing hepatic cell fates. Nat. Cell Biol. 24, 1487–1498 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. George, J., Goodwin, B., Liddle, C., Tapner, M. & Farrell Westmead, G. C. Time-dependent expression of cytochrome P450 genes in primary cultures of well-differentiated human hepatocytes. J. Lab. Clin. Med. 129, 638–648 (1997).

    Article  CAS  PubMed  Google Scholar 

  70. Hu, H. et al. Long-term expansion of functional mouse and human hepatocytes as 3D organoids. Cell 175, 1591–1606 (2018).

    Article  CAS  PubMed  Google Scholar 

  71. 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).

    Article  CAS  PubMed  Google Scholar 

  72. Prior, N. et al. Lgr5+ stem and progenitor cells reside at the apex of a heterogeneous embryonic hepatoblast pool. Development 146, dev174557 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Sugiyama, T. et al. Reconstituting pancreas development from purified progenitor cells reveals genes essential for islet differentiation. Proc. Natl Acad. Sci. USA 110, 12691–12696 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Greggio, C. et al. Artificial three-dimensional niches deconstruct pancreas development in vitro. Development 140, 4452–4462 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Bonfanti, P. et al. Ex vivo expansion and differentiation of human and mouse fetal pancreatic progenitors are modulated by epidermal growth factor. Stem Cell Dev. 24, 1766–1778 (2015).

    Article  CAS  Google Scholar 

  76. Andersson-Rolf, A. et al. Long-term in vitro expansion of a human fetal pancreas stem cell that generates all three pancreatic cell lineages. Cell 187, 7394–7413.e22 (2024).

    Article  CAS  PubMed  Google Scholar 

  77. Blanpain, C., Lowry, W. E., Geoghegan, A., Polak, L. & Fuchs, E. Self-renewal, multipotency, and the existence of two cell populations within an epithelial stem cell niche. Cell 118, 635–648 (2004).

    Article  CAS  PubMed  Google Scholar 

  78. Barker, N. et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449, 1003–1007 (2007).

    Article  CAS  PubMed  Google Scholar 

  79. Bonner-Weir, S. et al. In vitro cultivation of human islets from expanded ductal tissue. Proc. Natl Acad. Sci. USA 97, 7999–8004 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Nantasanti, S. et al. Disease modeling and gene therapy of copper storage disease in canine hepatic organoids. Stem Cell Rep. 5, 895–907 (2015).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  82. Roos, F. J. M. et al. Human branching cholangiocyte organoids recapitulate functional bile duct formation. Cell Stem Cell 29, 776–794.e13 (2022).

    Article  CAS  PubMed  Google Scholar 

  83. Peng, W. C. et al. Inflammatory cytokine TNFα promotes the long-term expansion of primary hepatocytes in 3D culture. Cell 175, 1607–1619.e15 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Dowbaj, A. M. et al. Mouse liver assembloids model periportal architecture and biliary fibrosis. Nature 644, 473–482 (2025).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Igarashi, R. et al. Generation of human adult hepatocyte organoids with metabolic functions. Nature 641, 1248–1257 (2025).

    Article  CAS  PubMed  Google Scholar 

  86. Yuan, L. et al. Human assembloids recapitulate periportal liver tissue in vitro. Preprint at Research Square https://doi.org/10.21203/rs.3.rs-5314788/v1 (2025).

  87. Georgia, S. & Bhushan, A. β cell replication is the primary mechanism for maintaining postnatal β cell mass. J. Clin. Investig. 114, 963–968 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Kopp, J. L. et al. Sox9+ ductal cells are multipotent progenitors throughout development but do not produce new endocrine cells in the normal or injured adult pancreas. Development 138, 653–665 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Solar, M. et al. Pancreatic exocrine duct cells give rise to insulin-producing β cells during embryogenesis but not after birth. Dev. Cell 17, 849–860 (2009).

    Article  CAS  PubMed  Google Scholar 

  90. Larsen, H. L. & Grapin-Botton, A. The molecular and morphogenetic basis of pancreas organogenesis. Semin. Cell Dev. Biol. 66, 51–68 (2017).

    Article  CAS  PubMed  Google Scholar 

  91. Grapin-Botton, A. & Kim, Y. H. Pancreas organoid models of development and regeneration. Development 149, dev201004 (2022).

    Article  CAS  PubMed  Google Scholar 

  92. Rovira, M. et al. Isolation and characterization of centroacinar/terminal ductal progenitor cells in adult mouse pancreas. Proc. Natl Acad. Sci. USA 107, 75–80 (2010).

    Article  CAS  PubMed  Google Scholar 

  93. Su, K. H., Cuthbertson, C. & Christophi, C. Review of experimental animal models of acute pancreatitis. HPB 8, 264–286 (2006).

    Article  PubMed  Google Scholar 

  94. Schuijers, J. & Clevers, H. Adult mammalian stem cells: the role of Wnt, Lgr5 and R-spondins. EMBO J. 31, 2685–2696 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Barker, N. et al. Lgr5+ve stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro. Cell Stem Cell 6, 25–36 (2010).

    Article  CAS  PubMed  Google Scholar 

  96. Bhushan, A. et al. Fgf10 is essential for maintaining the proliferative capacity of epithelial progenitor cells during early pancreatic organogenesis. Development 128, 5109–5117 (2001).

    Article  CAS  PubMed  Google Scholar 

  97. Fernández, Á. et al. A single-cell atlas of the murine pancreatic ductal tree identifies novel cell populations with potential implications in pancreas regeneration and exocrine pathogenesis. Gastroenterology 167, 944–960.e15 (2024).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  99. Loomans, C. J. M. et al. Expansion of adult human pancreatic tissue yields organoids harboring progenitor cells with endocrine differentiation potential. Stem Cell Rep. 10, 712–724 (2018).

    Article  Google Scholar 

  100. Cherubini, A. et al. Exploring human pancreatic organoid modelling through single-cell RNA sequencing analysis. Commun. Biol. 7, 1527 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Wang, D. et al. Long-term expansion of pancreatic islet organoids from resident Procr+ progenitors. Cell 180, 1198–1211.e19 (2020).

    Article  CAS  PubMed  Google Scholar 

  102. Heidenreich, A. C., Bacigalupo, L., Rossotti, M. & Rodríguez-Seguí, S. A. Identification of mouse and human embryonic pancreatic cells with adult Procr+ progenitor transcriptomic and epigenomic characteristics. Front. Endocrinol. 16, 1543960 (2025).

    Article  Google Scholar 

  103. Lee, J. et al. Expansion and conversion of human pancreatic ductal cells into insulin-secreting endocrine cells. eLife 2, e00940 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Xu, X. et al. β cells can be generated from endogenous progenitors in injured adult mouse pancreas. Cell 132, 197–207 (2008).

    Article  CAS  PubMed  Google Scholar 

  105. Gribben, C. et al. Ductal Ngn3-expressing progenitors contribute to adult β cell neogenesis in the pancreas. Cell Stem Cell 28, 2000–2008.e4 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Shao, W. et al. Advances in liver organoids: replicating hepatic complexity for toxicity assessment and disease modeling. Stem Cell Res. Ther. 16, 27 (2025).

    Article  PubMed  PubMed Central  Google Scholar 

  107. Wills, E. S. et al. Chromosomal abnormalities in hepatic cysts point to novel polycystic liver disease genes. Eur. J. Hum. Genet. 24, 1707–1714 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Guan, Y. et al. Human hepatic organoids for the analysis of human genetic diseases. JCI Insight 2, e94954 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  109. Mun, S. J. et al. Efficient and reproducible generation of human induced pluripotent stem cell-derived expandable liver organoids for disease modeling. Sci. Rep. 13, 22935 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Ortuño-Costela, M. C., Pinzani, M. & Vallier, L. Cell therapy for liver disorders: past, present and future. Nat. Rev. Gastroenterol. Hepatol. 22, 329–342 (2025).

    Article  PubMed  Google Scholar 

  111. Ouchi, R. et al. Modeling steatohepatitis in humans with pluripotent stem cell-derived organoids. Cell Metab. https://doi.org/10.1016/J.CMET.2019.05.007 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  112. Belenguer, G. et al. RNF43/ZNRF3 loss predisposes to hepatocellular-carcinoma by impairing liver regeneration and altering the liver lipid metabolic ground-state. Nat. Commun. 13, 334 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Jansen, P. L. M. et al. The ascending pathophysiology of cholestatic liver disease. Hepatology 65, 722–738 (2017).

    Article  CAS  PubMed  Google Scholar 

  115. Banales, J. M. et al. Cholangiocyte pathobiology. Nat. Rev. Gastroenterol. Hepatol. 16, 269–281 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  116. Hirschfield, G. M. et al. The genetics of complex cholestatic disorders. Gastroenterology 144, 1357–1374 (2013).

    Article  CAS  PubMed  Google Scholar 

  117. Mayer, C. et al. Apical bulkheads accumulate as adaptive response to impaired bile flow in liver disease. EMBO Rep. 24, e57181 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Amarachintha, S. P. et al. Biliary organoids uncover delayed epithelial development and barrier function in biliary atresia. Hepatology 75, 89–103 (2022).

    Article  CAS  PubMed  Google Scholar 

  119. Nie, Y. Z. et al. Recapitulation of hepatitis B virus–host interactions in liver organoids from human induced pluripotent stem cells. eBioMedicine 35, 114–123 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Lui, V. C. H. et al. Human liver organoid derived intra-hepatic bile duct cells support SARS-CoV-2 infection and replication. Sci. Rep. 12, 5375 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Broutier, L. et al. Human primary liver cancer-derived organoid cultures for disease modeling and drug screening. Nat. Med. 23, 1424–1435 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Nuciforo, S. et al. Organoid models of human liver cancers derived from tumor needle biopsies. Cell Rep. 24, 1363–1376 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. De Crignis, E. et al. Application of human liver organoids as a patient-derived primary model for HBV infection and related hepatocellular carcinoma. eLife 10, e60747 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  125. Yang, H. et al. Pharmacogenomic profiling of intra-tumor heterogeneity using a large organoid biobank of liver cancer. Cancer Cell 42, 535–551.e8 (2024).

    Article  CAS  PubMed  Google Scholar 

  126. 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).

    Article  PubMed  Google Scholar 

  127. Artegiani, B. et al. Probing the tumor suppressor function of BAP1 in CRISPR-engineered human liver organoids. Cell Stem Cell 24, 927–943.e6 (2019).

    Article  CAS  PubMed  Google Scholar 

  128. Hosein, A. N., Dougan, S. K., Aguirre, A. J. & Maitra, A. Translational advances in pancreatic ductal adenocarcinoma therapy. Nat. Cancer 3, 272–286 (2022).

    Article  PubMed  Google Scholar 

  129. Halbrook, C. J., Lyssiotis, C. A., Pasca di Magliano, M. & Maitra, A. Pancreatic cancer: advances and challenges. Cell 186, 1729–1754 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Niger, M. et al. One size does not fit all for pancreatic cancers: a review on rare histologies and therapeutic approaches. World J. Gastrointest. Oncol. 12, 833–849 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  131. Asa, S. L. Pancreatic endocrine tumors. Mod. Pathol. 24, S66–S77 (2011).

    Article  CAS  PubMed  Google Scholar 

  132. Tiriac, H. et al. Successful creation of pancreatic cancer organoids by means of EUS-guided fine-needle biopsy sampling for personalized cancer treatment. Gastrointest. Endosc. 87, 1474–1480 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  133. Bhalerao, N. et al. ST6GAL1 sialyltransferase promotes acinar to ductal metaplasia and pancreatic cancer progression. JCI Insight 8, e161563 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  134. Neal, J. T. et al. Organoid modeling of the tumor immune microenvironment. Cell 175, 1972–1988.e16 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. 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.e6 (2018).

    Article  CAS  PubMed  Google Scholar 

  136. Tamagawa, H. et al. Wnt-deficient and hypoxic environment orchestrates squamous reprogramming of human pancreatic ductal adenocarcinoma. Nat. Cell Biol. https://doi.org/10.1038/s41556-024-01498-5 (2024).

    Article  PubMed  Google Scholar 

  137. Papargyriou, A. et al. Heterogeneity-driven phenotypic plasticity and treatment response in branched-organoid models of pancreatic ductal adenocarcinoma. Nat. Biomed. Eng. https://doi.org/10.1038/s41551-024-01273-9 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  138. Ooi, C. Y. & Durie, P. R. Cystic fibrosis from the gastroenterologist’s perspective. Nat. Rev. Gastroenterol. Hepatol. 13, 175–185 (2016).

    Article  CAS  PubMed  Google Scholar 

  139. Hohwieler, M. et al. Human pluripotent stem cell-derived acinar/ductal organoids generate human pancreas upon orthotopic transplantation and allow disease modelling. Gut 66, 473–486 (2017).

    Article  CAS  PubMed  Google Scholar 

  140. O’Malley, Y. et al. Pancreatic duct organoid swelling is chloride-dependent. J. Cyst. Fibros. 23, 169–171 (2024).

    Article  PubMed  Google Scholar 

  141. Shapiro, A. M. J. et al. Insulin expression and C-peptide in type 1 diabetes subjects implanted with stem cell-derived pancreatic endoderm cells in an encapsulation device. Cell Rep. Med. 2, 100466 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Vegas, A. J. et al. Long-term glycemic control using polymer-encapsulated human stem cell-derived beta cells in immune-competent mice. Nat. Med. 22, 306–311 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Aghazadeh, Y. et al. Microvessels support engraftment and functionality of human islets and hESC-derived pancreatic progenitors in diabetes models. Cell Stem Cell 28, 1936–1949.e8 (2021).

    Article  CAS  PubMed  Google Scholar 

  144. Du, Y. et al. Human pluripotent stem-cell-derived islets ameliorate diabetes in non-human primates. Nat. Med. 28, 272–282 (2022).

    Article  PubMed  Google Scholar 

  145. Wang, S. et al. Transplantation of chemically induced pluripotent stem-cell-derived islets under abdominal anterior rectus sheath in a type 1 diabetes patient. Cell 187, 6152–6164.e18 (2024).

    Article  CAS  PubMed  Google Scholar 

  146. Choi, J. et al. Light-stimulated insulin secretion from pancreatic islet-like organoids derived from human pluripotent stem cells. Mol. Ther. 31, 1480–1495 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Huang, X. et al. Stomach-derived human insulin-secreting organoids restore glucose homeostasis. Nat. Cell Biol. 25, 778–786 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Zhang, X., Ma, Z., Song, E. & Xu, T. Islet organoid as a promising model for diabetes. Protein Cell 13, 239–257 (2022).

    Article  CAS  PubMed  Google Scholar 

  149. Beydag-Tasöz, B. S., Yennek, S. & Grapin-Botton, A. Towards a better understanding of diabetes mellitus using organoid models. Nat. Rev. Endocrinol. 19, 232–248 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  150. Meng, H. et al. FGF7 enhances the expression of ACE2 in human islet organoids aggravating SARS-CoV-2 infection. Signal. Transduct. Target. Ther. 9, 104 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Maxwell, K. G. et al. Gene-edited human stem cell-derived β cells from a patient with monogenic diabetes reverse preexisting diabetes in mice. Sci. Transl. Med. 12, eaax9106 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Ilegems, E. et al. HIF-1α inhibitor PX-478 preserves pancreatic β cell function in diabetes. Sci. Transl. Med. 14, eaba9112 (2022).

    Article  CAS  PubMed  Google Scholar 

  153. Ludwig, T. E. et al. ISSCR standards for the use of human stem cells in basic research. Stem Cell Rep. 18, 1744–1752 (2023).

    Article  CAS  Google Scholar 

  154. Elci, B. S., Nikolaev, M., Rezakhani, S. & Lutolf, M. P. Bioengineered tubular biliary organoids. Adv. Healthc. Mater. 13, e2302912 (2024).

    Article  PubMed  Google Scholar 

  155. Ben-Moshe, S. et al. Spatial sorting enables comprehensive characterization of liver zonation. Nat. Metab. 1, 899–911 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Panday, R., Monckton, C. P. & Khetani, S. R. The role of liver zonation in physiology, regeneration, and disease. Semin. Liver Dis. 42, 1–16 (2022).

    Article  PubMed  Google Scholar 

  157. Kietzmann, T. Metabolic zonation of the liver: the oxygen gradient revisited. Redox Biol. 11, 622–630 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Zhang, Y. et al. hESCs-derived organoids achieve liver zonation features through LSEC modulation. Adv. Sci. 12, e2411667 (2025).

    Article  Google Scholar 

  159. Al Reza, H. et al. Multi-zonal liver organoids from human pluripotent stem cells. Nature 641, 1258–1267 (2025).

    Article  PubMed Central  Google Scholar 

  160. Mallanna S. K. et al. Expandable, functional hepatocytes derived from primary cells enable liver therapeutics. Preprint at https://www.biorxiv.org/content/10.1101/2024.12.28.630269v1 (2024).

  161. Lee, B. H. et al. Control of lumen geometry and topology by the interplay between pressure and cell proliferation rate in pancreatic organoids. Preprint at https://www.biorxiv.org/content/10.1101/2024.05.29.596462v2 (2024).

  162. Deguchi, S. & Takayama, K. State-of-the-art liver disease research using liver-on-a-chip. Inflamm. Regener. 42, 62 (2022).

    Article  Google Scholar 

  163. Deng, J. et al. Engineered liver-on-a-chip platform to mimic liver functions and its biomedical applications: a review. Micromachines 10, 676 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  164. Hassan, S. et al. Liver-on-a-chip models of fatty liver disease. Hepatology 71, 733–740 (2020).

    Article  PubMed  Google Scholar 

  165. Ang, L. T. et al. A roadmap for human liver differentiation from pluripotent stem cells. Cell Rep. 22, 2190–2205 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Wu, F. et al. Generation of hepatobiliary organoids from human induced pluripotent stem cells. J. Hepatol. 70, 1145–1158 (2019).

    Article  PubMed  Google Scholar 

  167. Koike, H. et al. Modelling human hepato-biliary-pancreatic organogenesis from the foregut–midgut boundary. Nature 574, 112–116 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Akbari, S. et al. Robust, long-term culture of endoderm-derived hepatic organoids for disease modeling. Stem Cell Rep. 13, 627–641 (2019).

    Article  CAS  Google Scholar 

  169. Tadokoro, T. et al. Human iPSC-liver organoid transplantation reduces fibrosis through immunomodulation. Sci. Transl. Med. 16, eadg0338 (2024).

    Article  CAS  PubMed  Google Scholar 

  170. Marsee, A. et al. Mass generation and long-term expansion of hepatobiliary organoids from adult primary human hepatocytes. Preprint at bioRxiv https://doi.org/10.1101/2024.06.10.598262 (2024).

  171. Kanton, S. & Pasça, S. P. Human assembloids. Development 149, dev201120 (2022).

    Article  CAS  PubMed  Google Scholar 

  172. Hebb, D. O. The Organization of Behavior: A Neuropsychological Theory (Wiley, 1949).

  173. Andersen, J. et al. Generation of functional human 3D cortico-motor assembloids. Cell 183, 1913–1929.e26 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Bagley, J. A., Reumann, D., Bian, S., Lévi-Strauss, J. & Knoblich, J. A. Fused cerebral organoids model interactions between brain regions. Nat. Methods 14, 743–751 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Cordero-Espinoza, L. et al. Dynamic cell contacts between periportal mesenchyme and ductal epithelium act as a rheostat for liver cell proliferation. Cell Stem Cell https://doi.org/10.1016/j.stem.2021.07.002 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  176. Dowbaj, A. M., Kohler, T. N., Cordero-Espinoza, L., Hollfelder, F. & Huch, M. Generation of liver mesenchyme and ductal cell organoid co-culture using cell self-aggregation and droplet microfluidics. Star. Protoc. 4, 102333 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Yang, L. et al. Human vascularized macrophage-islet organoids to model immune-mediated pancreatic β cell pyroptosis upon viral infection. Cell Stem Cell 31, 1612–1629.e8 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Hughes, C. S., Postovit, L. M. & Lajoie, G. A. Matrigel: a complex protein mixture required for optimal growth of cell culture. Proteomics 10, 1886–1890 (2010).

    Article  CAS  PubMed  Google Scholar 

  179. Gan, Z., Qin, X., Liu, H., Liu, J. & Qin, J. Recent advances in defined hydrogels in organoid research. Bioactive Mater. 28, 386–401 (2023).

    Article  CAS  Google Scholar 

  180. Cao, Y. et al. Inclusion of cross-linked elastin in gelatin/PEG hydrogels favourably influences fibroblast phenotype. Polymers 12, 670 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Kapp, T. G. et al. A comprehensive evaluation of the activity and selectivity profile of ligands for RGD-binding integrins. Sci. Rep. 7, 39805 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Sorrentino, G. et al. Mechano-modulatory synthetic niches for liver organoid derivation. Nat. Commun. 11, 3416 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Garreta, E. et al. Rethinking organoid technology through bioengineering. Nat. Mater. 20, 145–155 (2021).

    Article  CAS  PubMed  Google Scholar 

  184. Belicova, L. et al. Anisotropic expansion of hepatocyte lumina enforced by apical bulkheads. J. Cell Biol. 220, e202103003 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Box, G. E. P. Science and statistics. J. Am. Stat. Assoc. 71, 791–799 (1976).

    Article  Google Scholar 

  186. Box, G. E. & Draper, N. R. Empirical Model-Building and Response Surfaces (Wiley, 1987).

Download references

Acknowledgements

N.P. is supported by the Academy of Medical Sciences Springboard Award (SBF007/100092) and Wessex Medical Research. J.G.J. is funded by the Gerald Kerkut Trust PhD studentship and Institute for Life Sciences, University of Southampton. M.H. is supported by the Max Planck Gessellschaft, and is funded by the European Research Council under the European Union’s Horizon Europe research and innovation programme (grant agreement no. 101088869), which also supports A.S. and A.N. The views and opinions expressed are, however, those of the author(s) only and do not necessarily reflect those of the European Union or the European Research Council. Neither the European Union nor the granting authority can be held responsible for the views and opinions expressed.

Author information

Author notes

  1. These authors contributed equally: Aleksandra Sljukic, Joshua Green Jenkinson, Armin Niksic.

Authors and Affiliations

  1. The Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany

    Aleksandra Sljukic, Armin Niksic & Meritxell Huch

  2. School of Biological Sciences, University of Southampton, Southampton, UK

    Joshua Green Jenkinson & Nicole Prior

  3. Center for Systems Biology (CSBD), Dresden, Germany

    Meritxell Huch

Authors
  1. Aleksandra Sljukic
    View author publications

    Search author on:PubMed Google Scholar

  2. Joshua Green Jenkinson
    View author publications

    Search author on:PubMed Google Scholar

  3. Armin Niksic
    View author publications

    Search author on:PubMed Google Scholar

  4. Nicole Prior
    View author publications

    Search author on:PubMed Google Scholar

  5. Meritxell Huch
    View author publications

    Search author on:PubMed Google Scholar

Contributions

The authors contributed equally to all aspects of the article.

Corresponding authors

Correspondence to Nicole Prior or Meritxell Huch.

Ethics declarations

Competing interests

M.H. is inventor in several patents related to organoid technology. M.H and A.S. are inventors in a patent on assembloids. The other authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Gastroenterology & Hepatology thanks Giuseppe Pettinato, Hasan Rashidi and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

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

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

Sljukic, A., Green Jenkinson, J., Niksic, A. et al. Advances in liver and pancreas organoids: how far we have come and where we go next. Nat Rev Gastroenterol Hepatol (2025). https://doi.org/10.1038/s41575-025-01116-1

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41575-025-01116-1

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer