Induced Pluripotent Stem Cell–derived Hepatocytes From Patients With Nonalcoholic Fatty Liver Disease Display a Disease-specific Gene Expression Profile

Duwaerts, Caroline C.; Guillou, Dounia Le; Her, Chris; Phillips, Nathaniel; Willenbring, Holger; Mattis, Aras N.; Maher, Jacquelyn J.

doi:10.1053/j.gastro.2021.02.050

Cited by 15 publications

(20 citation statements)

References 15 publications

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“…Interestingly, human iPSC-derived hepatocytes have recently been used in both 2D and 3D format to model NAFLD [252]. Another promising approach is the use of human iPSC-derived hepatocytes from patients with NAFLD including NASH, which might reproduce the inter-individual differences classically observed in DILI [253,254].…”

Section: Implications Of Dili In Clinical Contextsmentioning

confidence: 99%

Advanced preclinical models for evaluation of drug-induced liver injury – consensus statement by the European Drug-Induced Liver Injury Network [PRO-EURO-DILI-NET]

Fernández-Checa

Bagnaninchi

et al. 2021

Journal of Hepatology

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Section: Implications Of Dili In Clinical Contextsmentioning

confidence: 99%

Advanced preclinical models for evaluation of drug-induced liver injury – consensus statement by the European Drug-Induced Liver Injury Network [PRO-EURO-DILI-NET]

Fernández-Checa

Bagnaninchi

et al. 2021

Journal of Hepatology

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“…These findings are similar to recent work published using an iPS‐derived hepatocyte system to study nonalcoholic steatohepatitis‐related phenotypes. ( 8 )…”

Section: Resultsmentioning

confidence: 99%

Induced Pluripotent Stem Cells From Subjects With Primary Sclerosing Cholangitis Develop a Senescence Phenotype Following Biliary Differentiation

et al. 2021

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Primary sclerosing cholangitis (PSC) is a chronic fibroinflammatory disease of the biliary tract characterized by cellular senescence and periportal fibrogenesis. Specific disease features that are cell intrinsic and either genetically or epigenetically mediated remain unclear due in part to a lack of appropriate, patient-specific, in vitro models. Recently, our group developed systems to create induced pluripotent stem cell (iPSC)-derived cholangiocytes (iDCs) and biliary epithelial organoids (cholangioids). We use these models to investigate whether PSC cholangiocytes are intrinsically predisposed to cellular senescence. Skin fibroblasts from healthy controls and subjects with PSC were reprogrammed to pluripotency, differentiated to cholangiocytes, and subsequently grown in three-dimensional matrigel-based culture to induce formation of cholangioids. RNA sequencing (RNA-seq) on iDCs showed significant differences in gene expression patterns, including enrichment of pathways associated with cell cycle, senescence, and hepatic fibrosis, that correlate with PSC. These pathways also overlapped with RNA-seq analysis on isolated cholangiocytes from subjects with PSC. Exome sequencing on the subjects with PSC revealed genetic variants of unknown significance in the genes identified in these pathways. Three-dimensional culture revealed smaller size, lack of a central lumen, and increased cellular senescence in PSC-derived cholangioids. Congruent with this, PSC-derived iDCs showed increased secretion of the extracellular matrix molecule fibronectin as well as the inflammatory cytokines interleukin-6, and chemokine (C-C motif ) ligand 2. Conditioned media (CM) from PSC-derived iDCs more potently activated hepatic stellate cells compared to control CM. Conclusion: We demonstrated efficient generation of iDCs and cholangioids from patients with PSC that show disease-specific features. PSC cholangiocytes are intrinsically predisposed to cellular senescence. These features are unmasked following biliary differentiation of pluripotent stem cells and have functional consequences in epithelial organoids. (Hepatology Communications 2021;0:1-16).

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“…38 More recently, however, a study that generated and compared iHeps derived from NAFLD patients and healthy controls showed that NAFLD iHeps accumulated higher levels of lipids and upregulated genes associated with cell injury and death compared to control iHeps. 39 Since the study was done in vitro and without any impact from external factors such as diet or exercise, these findings suggest the presence of a genetic component to the development of NAFLD. 39 This, and many other studies, clearly establishes that NAFLD is a systemic, metabolic, and multifactorial disorder driven and influenced by the interaction of genetic and environmental components.…”

Section: Normal Ihepsmentioning

confidence: 96%

“…39 Since the study was done in vitro and without any impact from external factors such as diet or exercise, these findings suggest the presence of a genetic component to the development of NAFLD. 39 This, and many other studies, clearly establishes that NAFLD is a systemic, metabolic, and multifactorial disorder driven and influenced by the interaction of genetic and environmental components. Indeed, a recent initiative has proposed renaming NAFLD to metabolic dysfunction-associated fatty liver disease.…”

Section: Normal Ihepsmentioning

confidence: 96%

From a Single Cell to a Whole Human Liver: Disease Modeling and Transplantation

et al. 2022

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Although the underlying cause may vary across countries and demographic groups, liver disease is a major cause of morbidity and mortality globally. Orthotopic liver transplantation is the only definitive treatment for liver failure but is limited by the lack of donor livers. The development of drugs that prevent the progression of liver disease and the generation of alternative liver constructs for transplantation could help alleviate the burden of liver disease. Bioengineered livers containing human iPSC-derived liver cells are being utilized to study liver disease and to identify and test potential therapeutics. Moreover, bioengineered livers containing pig hepatocytes and endothelial cells have been shown to function and survive after transplantation into pig models of liver failure providing pre-clinical evidence toward future clinical applications. Finally, bioengineered livers containing human iPSC-derived liver cells have been shown to function and survive after transplantation in rodents but require considerable optimization and testing prior to clinical use. In conclusion, bioengineered livers have emerged as a suitable tool for modeling liver diseases and as a promising alternative graft for clinical transplantation. The integration of novel technologies and techniques for the assembly and analysis of bioengineered livers will undoubtedly expand future applications in basic research and clinical transplantation.

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Induced Pluripotent Stem Cell–derived Hepatocytes From Patients With Nonalcoholic Fatty Liver Disease Display a Disease-specific Gene Expression Profile

Cited by 15 publications

References 15 publications

Advanced preclinical models for evaluation of drug-induced liver injury – consensus statement by the European Drug-Induced Liver Injury Network [PRO-EURO-DILI-NET]

Advanced preclinical models for evaluation of drug-induced liver injury – consensus statement by the European Drug-Induced Liver Injury Network [PRO-EURO-DILI-NET]

Induced Pluripotent Stem Cells From Subjects With Primary Sclerosing Cholangitis Develop a Senescence Phenotype Following Biliary Differentiation

From a Single Cell to a Whole Human Liver: Disease Modeling and Transplantation

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