The liver organoid's past, present and future: a personalized medicine strategy

https://doi.org/10.53730/ijhs.v8nS1.14980

Authors

  • Mariam Abady Division of Chemical and Matrial Metrology, Korea Research Institute of Standards and Science, Yuseong-gu, Daejeon 34113, Republic of Korea | Department of Bio-Analytical Science, University of Science and Technology, 217 Gajeong-ro, Yuseong gu, Daejeon 34113, Republic of Korea | Department of Nutrition and Food Science, National Research Centre, Dokki, Cairo, 12622, Egypt
  • Ibrahim A. Zahran Chemistry Department, Faculty of Science, Helwan University, Ain Helwan, 11795, Cairo, Egypt
  • Yasmin Elmokhtar Physiology Department, Faculty of Dentistry, Pharos University in Alexandria, Alexandria, Egypt

Keywords:

Organoid, Stem cell model, liver development, modeling liver disease, personalized medicin

Abstract

Organoids are three-dimensional (3D) cell culture systems derived from human pluripotent stem cells or organotypic differentiation, replicating the complex interactions and functionalities of actual organs. These systems offer significant advantages for studying human tissue and organ biology, addressing limitations of animal models related to sample accessibility and ethical concerns. Liver organoids, in particular, are advanced models developed to study hepatic phenotypes, encompassing various cell types and enabling detailed investigation of cellular, molecular, and genetic aspects of liver diseases, drug metabolism, and protein secretion. They hold promise for fundamental research, drug discovery, and regenerative medicine applications. Despite their potential, organoids face limitations such as simplicity, lack of high-fidelity cell types, flexibility, and atypical physiology. Enhancements in organotypic liver-like surrogates, incorporating in vivo-like cell interactions and architecture, along with advancements in microfluidic chip technology, are expected to improve models for disease, toxicity, and drug discovery, paving the way for new treatments. This review will provide an overview of the history and development of liver organoids, their current progress, challenges, applications, and future prospects in the field of personalized medicine.

Downloads

Download data is not yet available.

References

Ober, E.A. and F.P. Lemaigre, Development of the liver: Insights into organ and tissue morphogenesis. Journal of hepatology, 2018. 68(5): p. 1049-1062.

Chi, K.Y. and J.-H. Kim, Recent advances in liver organoids and their use in in vitro modeling of non-alcoholic fatty liver disease. Organoid, 2022. 2.

Xie, Y., et al., Induction and maturation of hepatocyte-like cells in vitro: Focus on technological advances and challenges. Frontiers in Cell and Developmental Biology, 2021. 9: p. 765980.

Prior, N., P. Inacio, and M. Huch, Liver organoids: from basic research to therapeutic applications. Gut, 2019. 68(12): p. 2228-2237.

Takebe, T., et al., Massive and reproducible production of liver buds entirely from human pluripotent stem cells. Cell reports, 2017. 21(10): p. 2661-2670.

Ouchi, R. and H. Koike, Modeling human liver organ development and diseases with pluripotent stem cell-derived organoids. Frontiers in Cell and Developmental Biology, 2023. 11.

Huch, M., et al., The hope and the hype of organoid research. Development, 2017. 144(6): p. 938-941.

Coll, M., et al., Generation of hepatic stellate cells from human pluripotent stem cells enables in vitro modeling of liver fibrosis. Cell stem cell, 2018. 23(1): p. 101-113. e7.

Guan, Y., et al., A human multi-lineage hepatic organoid model for liver fibrosis. Nature communications, 2021. 12(1): p. 6138.

Lee, C.A., et al., Cryopreserved neonatal hepatocytes may be a source for transplantation: Evaluation of functionality toward clinical use. Liver Transplantation, 2018. 24(3): p. 394-406.

Afshari, A., et al., Different approaches for transformation of mesenchymal stem cells into hepatocyte-like cells. Stem cell research & therapy, 2020. 11(1): p. 1-14.

Nitta, S., et al., Conversion of mesenchymal stem cells into a canine hepatocyte-like cells by Foxa1 and Hnf4a. Regenerative Therapy, 2020. 14: p. 165-176.

Riveiro, A.R. and J.M. Brickman, From pluripotency to totipotency: an experimentalist's guide to cellular potency. Development, 2020. 147(16): p. dev189845.

Dakhore, S., B. Nayer, and K. Hasegawa, Human pluripotent stem cell culture: current status, challenges, and advancement. Stem cells international, 2018. 2018.

Sani, F., et al., Differentiation of menstrual blood derived stem cell (MensSCs) to hepatocyte-liked cell on three dimensional nanofiberscaffold: poly caprolacton (PCL). Journal of Biomedical Science and Engineering, 2016. 9(04): p. 216.

Xing, X., H. Feng, and Z. Yuan, Differentiation of bone mesenchymal stem cells into hepatocyte-like cells induced by liver tissue homogenate. Genet. Mol. Res, 2016. 15(3): p. 10.4238.

Cipriano, M., et al., The role of epigenetic modifiers in extended cultures of functional hepatocyte-like cells derived from human neonatal mesenchymal stem cells. Archives of toxicology, 2017. 91: p. 2469-2489.

Eipel, C., K. Abshagen, and B. Vollmar, Regulation of hepatic blood flow: the hepatic arterial buffer response revisited. Annals of Gastroenterology & Hepatology, 2011. 9(96).

Sambathkumar, R., et al., Generation of hepatocyte-and endocrine pancreatic-like cells from human induced endodermal progenitor cells. Plos one, 2018. 13(5): p. e0197046.

Chen, J., et al., The diversity and plasticity of adult hepatic progenitor cells and their niche. Liver International, 2017. 37(9): p. 1260-1271.

Liu, W., et al., Clonal expansion of hepatic progenitor cells and differentiation into hepatocyte‐like cells. Development, Growth & Differentiation, 2019. 61(3): p. 203-211.

Goulart, E., et al., Adult and iPS-derived non-parenchymal cells regulate liver organoid development through differential modulation of Wnt and TGF-β. Stem Cell Research & Therapy, 2019. 10(1): p. 1-11.

Olgasi, C., A. Cucci, and A. Follenzi, iPSC-derived liver organoids: a journey from drug screening, to disease modeling, arriving to regenerative medicine. International journal of molecular sciences, 2020. 21(17): p. 6215.

Kamishibahara, Y., et al., Stabilized generation of human iPSC-derived liver organoids using a modified coating approach. Biology Methods and Protocols, 2023. 8(1): p. bpac034.

Rogers, A.D., The biology of seamounts: 25 years on. Advances in marine biology, 2018. 79: p. 137-224.

Tachmatzidi, E.C., O. Galanopoulou, and I. Talianidis, Transcription control of liver development. Cells, 2021. 10(8): p. 2026.

Yamashita, T., et al., Billion-scale production of hepatocyte-like cells from human induced pluripotent stem cells. Biochemical and biophysical research communications, 2018. 496(4): p. 1269-1275.

Guicciardi, M.E., et al., The spectrum of reactive cholangiocytes in primary sclerosing cholangitis. Hepatology, 2020. 71(2): p. 741-748.

Ogawa, M., et al., Generation of functional ciliated cholangiocytes from human pluripotent stem cells. Nature communications, 2021. 12(1): p. 6504.

Zhang, Y., et al., Crosstalk between NK cells and hepatic stellate cells in liver fibrosis. Molecular Medicine Reports, 2022. 25(6): p. 1-7.

Seo, W. and W.-I. Jeong, Hepatic non-parenchymal cells: Master regulators of alcoholic liver disease? World journal of gastroenterology, 2016. 22(4): p. 1348.

MacParland, S.A., et al., Single cell RNA sequencing of human liver reveals distinct intrahepatic macrophage populations. Nature communications, 2018. 9(1): p. 4383.

Schutgens, F. and H. Clevers, Human organoids: tools for understanding biology and treating diseases. Annual Review of Pathology: Mechanisms of Disease, 2020. 15: p. 211-234.

Bar, S. and N. Benvenisty, Epigenetic aberrations in human pluripotent stem cells. The EMBO journal, 2019. 38(12): p. e101033.

Hicks, M.R. and A.D. Pyle, The emergence of the stem cell niche. Trends in Cell Biology, 2022.

Vining, K.H. and D.J. Mooney, Mechanical forces direct stem cell behaviour in development and regeneration. Nature reviews Molecular cell biology, 2017. 18(12): p. 728-742.

Akbari, S., et al., Next-generation liver medicine using organoid models. Frontiers in Cell and Developmental Biology, 2019. 7: p. 345.

Huch, M. and H. Gehart, van Boxtel R, Hamer K, Blokzijl F, Verstegen MM, et al. Long‐term culture of genome‐stable bipotent stem cells from adult human liver. Cell, 2015. 160: p. 299-312.

Guan, Y., et al., Human hepatic organoids for the analysis of human genetic diseases. JCI insight, 2017. 2(17).

Andersson, E.R., et al., Mouse model of Alagille syndrome and mechanisms of Jagged1 missense mutations. Gastroenterology, 2018. 154(4): p. 1080-1095.

Nie, Y.-Z., et al., Recapitulation of hepatitis B virus–host interactions in liver organoids from human induced pluripotent stem cells. EBioMedicine, 2018. 35: p. 114-123.

Baktash, Y., et al., Single particle imaging of polarized hepatoma organoids upon hepatitis C virus infection reveals an ordered and sequential entry process. Cell host & microbe, 2018. 23(3): p. 382-394. e5.

Artegiani, B., et al., Probing the tumor suppressor function of BAP1 in CRISPR-engineered human liver organoids. Cell Stem Cell, 2019. 24(6): p. 927-943. e6.

Yang, S., et al., Liver three-dimensional cellular models for high-throughput chemical testing. Cell Reports Methods, 2023. 3(3).

Caiazza, C., S. Parisi, and M. Caiazzo, Liver organoids: Updates on disease modeling and biomedical applications. Biology, 2021. 10(9): p. 835.

Nuciforo, S. and M.H. Heim, Organoids to model liver disease. JHEP Reports, 2021. 3(1): p. 100198.

Wang, Y. and X. Wang, Human ESC-derived Expandable Hepatic Organoids Enable Therapeutic Liver Repopulation and Pathophysiological Modeling of Alcoholic Liver Injury. HPB, 2021. 23: p. S46.

Younossi, Z., et al., Global perspectives on nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Hepatology, 2019. 69(6): p. 2672-2682.

Soret, P.-A., et al., In vitro and in vivo models of non-alcoholic fatty liver disease: a critical appraisal. Journal of clinical medicine, 2020. 10(1): p. 36.

McCarron, S., et al., Functional characterization of organoids derived from irreversibly damaged liver of patients with NASH. Hepatology, 2021. 74(4): p. 1825-1844.

Yuan, Y., et al., Engineered Platforms for Maturing Pluripotent Stem Cell-Derived Liver Cells for Disease Modeling. Cellular and Molecular Gastroenterology and Hepatology, 2023.

Heinecke, F., et al., The offspring from rats fed a fatty diet display impairments in the activation of liver peroxisome proliferator activated receptor alpha and features of fatty liver disease. Molecular and cellular endocrinology, 2020. 511: p. 110818.

Wang, Y., et al., Modeling human nonalcoholic fatty liver disease (NAFLD) with an organoids-on-a-chip system. ACS Biomaterials Science & Engineering, 2020. 6(10): p. 5734-5743.

Parola, M. and M. Pinzani, Liver fibrosis: Pathophysiology, pathogenetic targets and clinical issues. Molecular aspects of medicine, 2019. 65: p. 37-55.

Bao, Y.-l., et al., Animal and organoid models of liver fibrosis. Frontiers in physiology, 2021. 12: p. 666138.

Leite, S.B., et al., Novel human hepatic organoid model enables testing of drug-induced liver fibrosis in vitro. Biomaterials, 2016. 78: p. 1-10.

Jiang, S., et al., Development of a high-throughput micropatterned agarose scaffold for consistent and reproducible hPSC-derived liver organoids. Biofabrication, 2022. 15(1): p. 015006.

Kammala, A.K., et al., Expression of CYP450 enzymes in human fetal membranes and its implications in xenobiotic metabolism during pregnancy. Life Sciences, 2022. 307: p. 120867.

Marquardt, J.U. and J.B. Andersen, Liver cancer oncogenomics: opportunities and dilemmas for clinical applications. Hepatic oncology, 2015. 2(1): p. 79-93.

He, S., et al., PDXliver: a database of liver cancer patient derived xenograft mouse models. BMC cancer, 2018. 18: p. 1-9.

Zhang, R., et al., The biological process of lysine‐tRNA charging is therapeutically targetable in liver cancer. Liver International, 2021. 41(1): p. 206-219.

Kim, J.H., et al., Evolution of the multi-tRNA synthetase complex and its role in cancer. Journal of Biological Chemistry, 2019. 294(14): p. 5340-5351.

Baragaña, B., et al., Lysyl-tRNA synthetase as a drug target in malaria and cryptosporidiosis. Proceedings of the National Academy of Sciences, 2019. 116(14): p. 7015-7020.

Broutier, L., et al., Human primary liver cancer–derived organoid cultures for disease modeling and drug screening. Nature medicine, 2017. 23(12): p. 1424-1435.

Mun, S.J., et al., Generation of expandable human pluripotent stem cell-derived hepatocyte-like liver organoids. Journal of hepatology, 2019. 71(5): p. 970-985.

Shinozawa, T., et al., High-fidelity drug-induced liver injury screen using human pluripotent stem cell–derived organoids. Gastroenterology, 2021. 160(3): p. 831-846. e10.

Cheng, W., et al., Polystyrene microplastics induce hepatotoxicity and disrupt lipid metabolism in the liver organoids. Science of the Total Environment, 2022. 806: p. 150328.

Van de Wetering, M., et al., Prospective derivation of a living organoid biobank of colorectal cancer patients. Cell, 2015. 161(4): p. 933-945.

Hu, W. and M.A. Lazar, Modelling metabolic diseases and drug response using stem cells and organoids. Nature Reviews Endocrinology, 2022. 18(12): p. 744-759.

van den Berg, C.W., et al., Renal subcapsular transplantation of PSC-derived kidney organoids induces neo-vasculogenesis and significant glomerular and tubular maturation in vivo. Stem cell reports, 2018. 10(3): p. 751-765.

Huch, M., et al., Long-term culture of genome-stable bipotent stem cells from adult human liver. Cell, 2015. 160(1-2): p. 299-312.

AlFatah Mansour, A., et al., An in vivo model of functional and vascularized human brain organoids HHS Public Access Author manuscript. Nat Biotechnol, 2018. 36(5): p. 432-441.

Wang, Y.C., et al., Cell reprogramming in liver with potential clinical correlations. Journal of Digestive Diseases, 2022. 23(1): p. 13-21.

Kondo, J. and M. Inoue, Application of cancer organoid model for drug screening and personalized therapy. Cells, 2019. 8(5): p. 470.

Saito, Y., Establishment of an organoid bank of biliary tract and pancreatic cancers and its application for personalized therapy and future treatment. Journal of gastroenterology and hepatology, 2019. 34(11): p. 1906-1910.

De Siervi, S., et al., Patient-derived liver organoids as an in vitro model to study new personalized therapies targeting VDAC1 in intrahepatic cholangiocarcinoma. Digestive and Liver Disease, 2023. 55: p. S14.

Hendriks, D., et al., Establishment of human fetal hepatocyte organoids and CRISPR–Cas9-based gene knockin and knockout in organoid cultures from human liver. Nature Protocols, 2021. 16(1): p. 182-217.

Zhan, T., et al. CRISPR/Cas9 for cancer research and therapy. in Seminars in cancer biology. 2019. Elsevier.

Ringel, T., et al., Genome-scale CRISPR screening in human intestinal organoids identifies drivers of TGF-β resistance. Cell stem cell, 2020. 26(3): p. 431-440. e8.

Jeon, W., et al., Evaluation of Radiation Sensitivity Differences in Mouse Liver Tumor Organoids Using CRISPR/Cas9-Mediated Gene Mutation. Technology in Cancer Research & Treatment, 2023. 22: p. 15330338231165125.

Zhang, Y.S., et al., 3D bioprinting for tissue and organ fabrication. Annals of biomedical engineering, 2017. 45: p. 148-163.

Bhise, N.S., et al., A liver-on-a-chip platform with bioprinted hepatic spheroids. Biofabrication, 2016. 8(1): p. 014101.

Jin, Y., et al., Vascularized liver organoids generated using induced hepatic tissue and dynamic liver‐specific microenvironment as a drug testing platform. Advanced Functional Materials, 2018. 28(37): p. 1801954.

Schepers, A., et al., Engineering a perfusable 3D human liver platform from iPS cells. Lab on a Chip, 2016. 16(14): p. 2644-2653.

Chung, M., et al., Biomimetic model of tumor microenvironment on microfluidic platform. Advanced healthcare materials, 2017. 6(15): p. 1700196.

Wang, Y., et al., In situ differentiation and generation of functional liver organoids from human iPSCs in a 3D perfusable chip system. Lab on a Chip, 2018. 18(23): p. 3606-3616.

Ingber, D.E., Human organs-on-chips for disease modelling, drug development and personalized medicine. Nature Reviews Genetics, 2022. 23(8): p. 467-491.

Abady, M.M., et al., The reprotoxic adverse side effects of neurogenic and neuroprotective drugs: current use of human organoid modeling as a potential alternative to preclinical models. Frontiers in Pharmacology, 2024. 15: p. 1412188.

Du, Y., et al., A bile duct‐on‐a‐chip with organ‐level functions. Hepatology, 2020. 71(4): p. 1350-1363.

Chen, X., et al., Organ-on-a-chip platforms for accelerating the evaluation of nanomedicine. Bioactive Materials, 2021. 6(4): p. 1012-1027.

Abady, M.M., J.-S. Jeong, and H.-J. Kwon, Development and validation of an analytical method using liquid chromatography-tandem mass spectrometry for the therapeutic drug monitoring of seven cardiovascular drugs in clinical usage. Journal of Chromatography B, 2023. 1214: p. 123552.

Abady, M.M., J.-S. Jeong, and H.-J. Kwon, Simultaneous quantification of 11 antiepileptic drugs using limited isotope-labeled internal standards in LC-MS/MS: An accuracy assessment. Journal of Chromatography B, 2024. 1240: p. 124143.

Abady, M.M., J.-S. Jeong, and H.-J. Kwon, Dried blood spot sampling coupled with liquid chromatography-tandem mass for simultaneous quantitative analysis of multiple cardiovascular drugs. Journal of Chromatography B, 2024. 1242: p. 124215.

Kogler, S., et al., Organoids, organ-on-a-chip, separation science and mass spectrometry: An update. TrAC Trends in Analytical Chemistry, 2023. 161: p. 116996.

Lee, J., et al., Advances in liver organoids: model systems for liver disease. Archives of Pharmacal Research, 2022. 45(6): p. 390-400.

Lieshout, R., et al., Kinome profiling of cholangiocarcinoma organoids reveals potential druggable targets that hold promise for treatment stratification. Molecular Medicine, 2022. 28(1): p. 1-15.

He, C., et al., Liver Organoids, Novel and Promising Modalities for Exploring and Repairing Liver Injury. Stem Cell Reviews and Reports, 2023. 19(2): p. 345-357.

Sun, X.-C., et al., Liver organoids: established tools for disease modeling and drug development. Hepatology Communications, 2023. 7(4): p. e0105.

Liu, Y., et al., A decade of liver organoids: Advancements in disease modeling. Clinical and Molecular Hepatology, 2023.

De Siervi, S. and C. Turato, Liver Organoids as an In Vitro Model to Study Primary Liver Cancer. International Journal of Molecular Sciences, 2023. 24(5): p. 4529.

Roman, G., et al., iPSC-derived liver organoids and inherited bleeding disorders: Potential and future perspectives. Frontiers in Physiology, 2023. 14: p. 4.

Yang, X., et al., Single‐cell profiling reveals distinct immune phenotypes that contribute to ischaemia‐reperfusion injury after steatotic liver transplantation. Cell Proliferation, 2021. 54(10): p. e13116.

Rossi, G., A. Manfrin, and M.P. Lutolf, Progress and potential in organoid research. Nature Reviews Genetics, 2018. 19(11): p. 671-687.

Schneeberger, K., et al., Large‐scale production of LGR5‐positive bipotential human liver stem cells. Hepatology, 2020. 72(1): p. 257-270.

Unagolla, J.M. and A.C. Jayasuriya, Recent advances in organoid engineering: A comprehensive review. Applied Materials Today, 2022. 29: p. 101582.

Caralt, M., et al., Liver bioengineering: from the stage of liver decellularized matrix to the multiple cellular actors and bioreactor special effects. Organogenesis, 2014. 10(2): p. 250-259.

Bernal, P.N., et al., Volumetric bioprinting of organoids and optically tuned hydrogels to build liver‐like metabolic biofactories. Advanced Materials, 2022. 34(15): p. 2110054.

Pang, Y., et al., Organization of liver organoids using Raschig ring-like micro-scaffolds and triple co-culture: Toward modular assembly-based scalable liver tissue engineering. Medical Engineering & Physics, 2020. 76: p. 69-78.

Yin, X., et al., Engineering stem cell organoids. Cell stem cell, 2016. 18(1): p. 25-38.

Park, S.E., A. Georgescu, and D. Huh, Organoids-on-a-chip. Science, 2019. 364(6444): p. 960-965.

Li, J., et al., The mechanisms and strategies to protect from hepatic ischemia-reperfusion injury. Eur Rev Med Pharmacol Sci, 2015. 19(11): p. 2036-2047.

Wang, K., et al., Severity of early allograft dysfunction following donation after circulatory death liver transplantation: a multicentre study. Hepatobiliary Surgery and Nutrition, 2021. 10(1): p. 9.

DuBray Jr, B.J., et al., Novel in vitro model for studying hepatic ischemia-reperfusion injury using liver cubes. Surgery, 2012. 152(2): p. 247-253.

Módis, K., et al., Adenosine and inosine exert cytoprotective effects in an in vitro model of liver ischemia-reperfusion injury. International Journal of Molecular Medicine, 2013. 31(2): p. 437-446.

DeForest, C.A., B.D. Polizzotti, and K.S. Anseth, Sequential click reactions for synthesizing and patterning three-dimensional cell microenvironments. Nature materials, 2009. 8(8): p. 659-664.

Ye, S., et al., A chemically defined hydrogel for human liver organoid culture. Advanced functional materials, 2020. 30(48): p. 2000893.

Abady, M.M., et al., Chapter 4 - Nanobiotechnology for the food industry: Current scenario, risk assessment, and management, in Nanobiotechnology for Food Processing and Packaging, J. Singh, et al., Editors. 2024, Academic Press. p. 65-94.

Elella, M.H.A., et al., Nanographites as Multidimensional Carriers for Advanced Therapeutic Applications, in Carbon Nanostructures in Biomedical Applications. 2023, Springer. p. 67-93.

Saleh, S.R., et al., Berberine nanoencapsulation attenuates hallmarks of scoplomine induced Alzheimer's-like disease in rats. Current Reviews in Clinical and Experimental Pharmacology Formerly Current Clinical Pharmacology, 2021. 16(2): p. 139-154.

Sato, T., et al., Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett's epithelium. Gastroenterology, 2011. 141(5): p. 1762-1772.

Kim, J., B.-K. Koo, and J.A. Knoblich, Human organoids: model systems for human biology and medicine. Nature Reviews Molecular Cell Biology, 2020. 21(10): p. 571-584.

De Masi, C., et al., Application of CRISPR/Cas9 to human-induced pluripotent stem cells: from gene editing to drug discovery. Human genomics, 2020. 14(1): p. 1-12.

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

Published

05-08-2024

How to Cite

Abady, M., Zahran, I. A., & Elmokhtar, Y. (2024). The liver organoid’s past, present and future: a personalized medicine strategy. International Journal of Health Sciences, 8(S1), 972–998. https://doi.org/10.53730/ijhs.v8nS1.14980

Issue

Section

Peer Review Articles