Aug 2026· Cell Proliferation· 0 citations· 100 references
Medicine
TL;DR
This review systematically summarises current fabrication strategies, disease‐modelling utilities and regenerative potentials of liver organoids, alongside the major challenges and future directions.
Abstract
ABSTRACT Liver organoids are three‐dimensional miniature liver models that recapitulate the complex architecture and key functions of the human liver in vitro, offering powerful platforms for both fundamental research and translational applications. This review systematically summarises current fabrication strategies, disease‐modelling utilities and regenerative potentials of liver organoids, alongside the major challenges and future directions. In recent years, the field has witnessed several breakthroughs. Through endothelial co‐culture approaches, vascularised and metabolically zonated liver organoids have been successfully generated, achieving endothelial coverage exceeding 85%. Prime editing enables precise correction of pathogenic mutations in patient‐derived organoids, with no off‐target effects detected at the genome‐wide level. In disease modelling, iPSC‐derived liver organoids faithfully recapitulate the pathological progression of metabolic dysfunction‐associated steatotic liver disease (MASLD) and verify the lipid‐lowering efficacy of semaglutide. Macrophage‐integrated organoid models support the full life cycles of HEV, SARS‐CoV‐2 and dengue virus, providing new tools for antiviral drug screening. Large‐scale patient‐derived tumour organoid biobanks successfully preserve the heterogeneity and clinical drug‐resistance signatures of liver cancers. In regenerative medicine, encapsulated hepatocyte organoids and the UTOpiA bioartificial liver system have effectively rescued acute liver failure in animal models, while gene‐edited autologous organoids offer potential curative strategies for genetic disorders such as Wilson disease. Nevertheless, insufficient hepatocyte functional maturity, difficulties in constructing vascular networks, and the lack of standardised culture protocols remain major obstacles to clinical translation. By bridging fundamental liver biology and clinical practice, liver organoid technology lays a solid foundation for precision hepatology and regenerative therapies. Continued interdisciplinary efforts are still required to overcome current limitations and facilitate its clinical adoption.
Liver organoids have rapidly advanced as human-relevant systems for modeling liver development, metabolic disease, and drug responses. Recent studies have established expandable adult hepatocyte organoids with sustained proliferative capacity, engineered induced pluripotent stem cell-derived organoids exhibiting metabolic zonation through controlled signaling gradients, and constructed multicellular assembloids that incorporate non-parenchymal cell types to recapitulate physiological periportal architecture and model cholestatic fibrotic microenvironments. These developments have enhanced scalability, structural organization, and disease modeling fidelity, supporting applications in translational research. Despite these advances, several challenges remain. Current evaluation of liver organoids largely relies on terminal functional outputs, while the upstream regulatory hierarchies that specify hepatic identity, zonation, and metabolic competence remain insufficiently reconstructed and validated. Limitations in long-term stability, spatial precision, and standardization further constrain predictive performance. This Review summarizes recent technological progress, discusses strategies to improve regulatory fidelity and functional benchmarking, and outlines future directions toward developing liver organoids as more reliable platforms for disease modeling and precision hepatology.
Xi Xu, Caimeng Zhuang, Yuchen Liu et al.· The Innovation Drug Discover...· 0 citations
ABSTRACT Organoids derived from human induced pluripotent stem cells (iPSCs) serve as advanced multicellular models for studying human organ development and disease. Recent liver organoid platforms focus on achieving multicellular organization while minimizing reliance on xenogeneic extracellular matrices to support future clinical translation. Building on these advances, this study establishes a xenogeneic‐free strategy that develops the hepatic cellular repertoire with interdigitating vasculature using an air‐liquid interface approach, generating highly vascularized, multicellular, and functional liver organoids from de‐identified control and metabolic dysfunction‐associated steatohepatitis (MASH) donor‐derived iPSCs. Phenotypic and functional characterization confirms the presence of hepatocytes, cholangiocytes, stellate cells, sinusoidal endothelial cells, and Kupffer‐like cells. These organoids demonstrate the capacity to model steatohepatitis following free‐fatty acid exposure and predict acetaminophen‐induced drug toxicity. Organoids derived from MASH‐donors exhibit increased susceptibility to steatosis, inflammation, fibrosis, and acetaminophen‐induced toxicity. Lipidomic profiling reveals that MASH phenotype in organoids induces global lipidomic shifts that closely resemble those observed in MASH liver biopsies. Further post‐transplantation into mice, the organoids retain hepatic cell repertoire, establish functional anastomoses with host vasculature, display intraluminal erythrocytes, and secrete human‐specific albumin, validating their translational potential. This approach provides a robust, xenogeneic‐free platform for disease modeling, evaluating drug responses, and exploring regenerative therapies.
Ekta Minocha, A. Gupta, Nate Schmidt et al.· Advancement of science· 0 citations
Organoid technology has emerged as a powerful platform for modeling human development, disease, and drug responses. Advances in stem cell biology and bioengineering have enabled the generation of increasingly sophisticated organoid systems that recapitulate key structural and cellular features of native tissues. However, despite substantial progress, the translational impact of organoids in regenerative medicine remains limited. Greater structural complexity and anatomical resemblance have not consistently translated into sustained therapeutic function or clinical applicability. Major barriers include incomplete maturation, inadequate vascular and immune integration, limited long-term functional stability, and challenges in reproducibility and scalability. These limitations reflect a conceptual mismatch between structure-driven organoid development and the functional requirements of regenerative medicine. Here, we propose a function-first framework in which regenerative organoids are engineered and evaluated according to measurable therapeutic outcomes, including tissue-specific function, vascular integration, immune compatibility, reproducibility, scalability, and long-term stability. We further discuss emerging bioengineering strategies, including vascularization, immune incorporation, organ-on-a-chip platforms, advanced biomaterials, and automated manufacturing, that may accelerate clinical translation. Reframing organoids as functionally engineered therapeutic platforms rather than increasingly complex anatomical models provides a conceptual foundation for advancing regenerative organoid therapies.
Liver tissue engineering offers a promising alternative for end-stage liver disease, yet the recreation of functional vasculature remains a major bottleneck to clinical translation. Here, we developed vascularized liver organoids by integrating human induced pluripotent stem cell (iPSC)–derived hepatoblasts and endothelial cells into decellularized scaffolds functionalized with an anti-CD31 aptamer–based vascular coating agent (VCA). This facilitated spatially coordinated organization of vasculature and parenchyma. Spatial transcriptomic profiling and subsequent functional perturbation demonstrated IGF2-IGF1R-AKT/MAPK signaling as a key axis governing spatial organization and functional maturation of the liver organoids. Furthermore, exogenous IGF2 synergized with the VCA to augment the structural and functional refinement of liver organoids, which translated into markedly improved therapeutic outcomes following transplantation into a chronic liver failure mouse model. Collectively, these findings establish a comprehensive framework for generating physiologically relevant liver tissues from iPSCs and demonstrate the utility of spatial transcriptomics for uncovering regenerative mechanisms. This approach advances the feasibility of autologous, transplantable liver grafts for personalized regenerative therapy.
Da-Hyun Kim, Yongju Lee, Min-Ji Kim et al.· Science Advances· 0 citations
Kidney organoids are important tools for modeling human development and disease, especially in chronic kidney disease (CKD), which is a global health challenge. Current treatment strategies focus on delaying disease progression by managing underlying causes, and in this regard, kidney organoids offer a platform for mechanism-based therapeutics. Advances in the understanding of human induced pluripotent stem cells (hiPSCs) and sophisticated 3D organ culture methods have enabled researchers to replicate human kidney development and disease mechanisms in vitro, thereby opening new avenues for drug testing. Although the methods for generating renal cell lineages are well established, new protocols for inducing lineages, such as the ureteric bud and collecting ducts, have emerged over the past 5 years. Patient-derived or genetically edited kidney organoids have been used to successfully model various genetic kidney diseases, notably polycystic kidney disease, and to generate kidney tissues that closely mimic the morphology of real organs. However, achieving more complex disease modeling and generating transplantable synthetic kidneys still has notable challenges. The present review discusses the application of hiPSC-derived 3D organoids in CKD research and addresses the limitations of current organ culture methods. The present review also examines the impact of CRISPR/Cas9 technology, and investigates potential future directions.
Shengxin Cui, Ti-Chou Chen, Yun Zou et al.· Experimental and Therapeutic...· 0 citations
Cardiovascular disease (CVD) represents a major global public health burden. Traditional research models struggle to meet the demands of elucidating disease mechanisms and advancing drug development due to limitations such as species differences. Cardiac organoids, with their high physiological fidelity, have emerged as alternative models. Cardiac organoids demonstrate unique value in modeling various diseases such as myocardial infarction, heart failure, and cardiomyopathy, and are widely applied in drug toxicity assessment and regenerative medicine research. The integration of artificial intelligence technology with cardiac organoids has enabled intelligent upgrades in organoid construction optimization and multidimensional monitoring analysis, significantly enhancing research efficiency and precision. This review summarizes the application progress of cardiac organoids in CVD research, outlining their developmental prospects in precision medicine and drug discovery. High-Fidelity Disease Modeling: cardiac organoids bridge animal models and human clinical states by recapitulating 3D architecture and physiology of diverse cardiovascular diseases. Superior Drug Toxicity Assessment: 3D cardiac organoids outperform 2D cultures in functional drug toxicity sensitivity/predictability, enabling scalable human-specific high-throughput safety screening. AI-Enabled Multidimensional Monitoring: AI (deep learning, cGANs) enables non-invasive, label-free, high-throughput quantitative analysis of organoid morphology, contractility and inflammation. High-Fidelity Disease Modeling: cardiac organoids bridge animal models and human clinical states by recapitulating 3D architecture and physiology of diverse cardiovascular diseases. Superior Drug Toxicity Assessment: 3D cardiac organoids outperform 2D cultures in functional drug toxicity sensitivity/predictability, enabling scalable human-specific high-throughput safety screening. AI-Enabled Multidimensional Monitoring: AI (deep learning, cGANs) enables non-invasive, label-free, high-throughput quantitative analysis of organoid morphology, contractility and inflammation.
Bolin Jiao, Yachen Hou, Pengchong Du et al.· Med-X· 0 citations
A new method for surgically removing training examples from a model reveals that as datasets grow, the link between what a model learns and what it produces dissolves.
MIT News · Artificial Intelligence· news.mit.eduAug 17, 2026
