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Organoids to model liver disease.

ABSTRACT: The organoid model represents a major breakthrough in cell biology that has revolutionised biomedical research. Organoids are 3D physiological in vitro structures that recapitulate morphological and functional features of in vivo tissues and offer significant advantages over traditional cell culture methods. Liver organoids are of particular interest because of the pleiotropy of functions exerted by the human liver, their utility to model different liver diseases, and their potential application as cell-based therapies in regenerative medicine. Moreover, because they can be derived from patient tissues, organoid models offer new perspectives in personalised medicine and drug discovery. In this review, we discuss the current liver organoid models for the study of liver disease.

SUBMITTER: Nuciforo S

PROVIDER: S-EPMC7672322 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Organoids to model liver disease.

Nuciforo Sandro S Heim Markus H MH

JHEP reports : innovation in hepatology 20201022 1

The organoid model represents a major breakthrough in cell biology that has revolutionised biomedical research. Organoids are 3D physiological <i>in vitro</i> structures that recapitulate morphological and functional features of <i>in vivo</i> tissues and offer significant advantages over traditional cell culture methods. Liver organoids are of particular interest because of the pleiotropy of functions exerted by the human liver, their utility to model different liver diseases, and their potenti ...[more]

PMID: 33241206

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Project description:Background & aimsPatient-derived tumor organoids recapitulate the characteristics of colorectal cancer (CRC) and provide an ideal platform for preclinical evaluation of personalized treatment options. We aimed to model the acquisition of chemotolerance during first-line combination chemotherapy in metastatic CRC organoids.MethodsWe performed next-generation sequencing to study the evolution of KRAS wild-type CRC organoids during adaptation to irinotecan-based chemotherapy combined with epidermal growth factor receptor (EGFR) inhibition. Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 protein (Cas9)-editing showed the specific effect of KRASG12D acquisition in drug-tolerant organoids. Compound treatment strategies involving Aurora kinase A (AURKA) inhibition were assessed for their capability to induce apoptosis in a drug-persister background. Immunohistochemical detection of AURKA was performed on a patient-matched cohort of primary tumors and derived liver metastases.ResultsAdaptation to combination chemotherapy was accompanied by transcriptomic rather than gene mutational alterations in CRC organoids. Drug-tolerant cells evaded apoptosis and up-regulated MYC (c-myelocytomatosis oncogene product)/E2F1 (E2 family transcription factor 1) and/or interferon-α-related gene expression. Introduction of KRASG12D further increased the resilience of drug-persister CRC organoids against combination therapy. AURKA inhibition restored an apoptotic response in drug-tolerant KRAS-wild-type organoids. In dual epidermal growth factor receptor (EGFR)- pathway blockade-primed CRC organoids expressing KRASG12D, AURKA inhibition augmented apoptosis in cases that had acquired increased c-MYC protein levels during chemotolerance development. In patient-matched CRC cohorts, AURKA expression was increased in primary tumors and derived liver metastases.ConclusionsOur study emphasizes the potential of patient-derived CRC organoids in modeling chemotherapy tolerance ex vivo. The applied therapeutic strategy of dual EGFR pathway blockade in combination with AURKA inhibition may prove effective for second-line treatment of chemotolerant CRC liver metastases with acquired KRAS mutation and increased AURKA/c-MYC expression.

Project description:Chronic liver injury promotes fibrosis, which can progress to cirrhosis, a major cause of morbidity and mortality worldwide. Resolving the cell-type-specific transcriptional changes orchestrating this transformation remains challenging. Recent advances in differentiation protocols allow the generation of multi-lineage human liver organoids (HLOs) from human pluripotent stem cells (hPSCs), providing a new model system to study evolving liver injury. We differentiated hPSCs into HLOs and defined optimal 3D culture conditions for liver injury induction. We modeled steatohepatitis through treatment with palmitic acid (PA) and fibrotic injury through treatment with transforming growth factor beta 1 (TGF-β1). For each injury type, we evaluated the development of fibrosis and inflammation by monitoring changes in morphology, gene expression, and histology. We then performed single-cell RNA-sequencing (scRNA-seq) to investigate cell-type diversity in healthy organoids at different time-points and to understand how TGF-β1- and PA-mediated injury affects each cell type. We observed transcriptional response signatures in injured HLOs to be both cell-type- and injury-specific. TGF-β1 treatment expanded hepatic stellate cell (HSC)-like populations and remodeled cell-cycle patterning. Gene set scoring revealed increased fibroblast activity with TGF-β1 treatment, while PA treatment was associated with inflammatory activity. Differential gene expression analysis at the subpopulation level showed induced profibrotic and extracellular matrix-remodeling pathways with TGF-β1 and non-alcoholic fatty liver disease (NAFLD) expression signatures with PA treatment. Evaluation of receptor and ligand expression defined hepatocyte-, cholangiocyte-, and HSC-like cell-cell interactions induced upon TGF-β1 treatment, an effect not observed with PA treatment. Tracing the changes at receptor-ligand pair resolution revealed specific COL1A1-Integrin complex interactions with TGF-β1 treatment and inflammation-specific interactions including CXCR7 and HLA-C with PA treatment. Treatment of HLOs with PA and TGF-β1 also demonstrated a sequential increase in expression of gene sets that predict clinical disease progression in non-alcoholic steatohepatitis (NASH). Our results demonstrate the applicability of hPSC-derived HLOs as a dynamic in vitro 3D human liver model system for the study of fibrotic and inflammatory liver injury.

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Organoids to model liver disease.

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Organoids to model liver disease.

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