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Patient-derived liver organoids recapitulate epithelial heterogeneity and enable precision disease modelling of alcohol-associated liver disease

ABSTRACT: Organoids are emerging as a powerful human-based in vitro tool in the biomedical field. However, patient-derived liver organoids fail to recapitulate the liver epithelial heterogeneity and its generation still requires liver surgical resections, thus limiting personalized chronic liver diseases modeling. Here, we report the derivation of organoids from intact liver needle biopsies(b-Orgs) from alcohol-associated liver disease (ALD) patients for precision disease modeling and drug testing. B-Orgs were generated with an efficiency of 80% from patients with early and advanced stages of ALD. b-Orgs show an enriched hepatocyte phenotype as assessed by immunofluorescence, functional studies, and transcriptomics. Single cell RNA-sequencing revealed a heterogeneous epithelial composition comprising hepatocyte, biliary and progenitor hepatobiliary populations, mirroring the epithelial populations found in advanced ALD patients. Moreover, b-Orgs preserve disease-stage features, as b-Orgs from advanced ALD patients showed increased expression of genes related to epithelial-mesenchymal transition, angiogenesis and inflammation. Stimulation of b-Orgs with ethanol and pro-inflammatory mediators,promoted ALD features such asROS production, lipid accumulation, inflammation and decreased proliferation, which were mitigated in response to prednisolone. Overall, we provide a new methodology to obtain b-Orgs showing epithelial complexity and patient specific features, thus expanding organoid-based liver disease modelling for personalized medicine.

ORGANISM(S): Homo sapiens

PROVIDER: GSE273146 | GEO | 2026/01/02

REPOSITORIES: GEO

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Project description:Background & Aims: The increasing requirements for hepatocytes in therapeutics and pharmacy call for an efficient system that enables large-scale production of functional hepatocytes in vitro. Hepatoblast (HB) hold the ability to regenerate liver when damaged, combined with organoid (org) technology, the culture of human pluripotent stem cell (hPSCs) derived HB-orgs was established under 2D culture system, enabling long-term expansion of HB in vitro. However, the expensive cost and the limitation of existing methods impede the further scale up of the production. Methods: Under 3D suspension culture conditions with the support of Matrigel at low concentration in conjunction with employing the developed (defined) medium, we developed a novel system to efficiently and reproducibly generate expandable HB-orgs and functional polarized hepatocyte organoids (P-hep-orgs) derived from hESCs. HB-orgs were further scaled up by dynamic culture in spinner flasks, and the maturity and function of P-hep-orgs was validated by transcriptome analysis and in vitro and in vivo hepatic functional assays. scRNA-seq was used to further profile HB-orgs and P-hep-orgs. Results: Our HB-orgs exhibited biopotency that could differentiate into functional hepatocytes and cholangiocytes. They proliferated actively at least for 15 passages with defined medium through avoiding the excessive autophagy under 3D suspension culture condition. HB-orgs showed higher proliferation rate in dynamic culture conditions and could reach 10^12 cell number at the initiate number of 3 million cells in only 4 weeks. With further differentiation, P-hep-orgs displayed characteristics of hepatocytes in liver, including the polarization state which mediated by integrin-AMPK signalling pathway, molecular features and improved liver functions. Moreover, P-hep-orgs were used for predicting the toxicity of various compounds, and modeling the development of hepatic lipid accumulation, as well as rescuing acute liver failure of mice. Conclusion: Our work provided a cost-efficient method for large-scale generation of 3D HB-orgs and 3D P-hep-orgs that hold considerable potential to be a robust platform for disease research, drug screening/development and toxic study, as well as clinical applications.

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Patient-derived liver organoids recapitulate epithelial heterogeneity and enable precision disease modelling of alcohol-associated liver disease

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