Modeling Nonalcoholic Fatty Liver Disease in the Dish Using Human-Specific Platforms: Strategies and Limitations

Rezvani, Milad; Vallier, Ludovic; Guillot, Adrien

doi:10.1016/j.jcmgh.2023.01.014

Cited by 8 publications

(8 citation statements)

References 82 publications

(104 reference statements)

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“…On the contrary, 3D culture approaches, particularly organoids, allow the generation of more complex structures that to obtain different cell types that make up the liver and demonstrate the high potential of these models for the study of complex metabolic diseases relying on the interactions of several cell types. 10,31 Several techniques have been developed for the formation of organoids from stem cells or differentiated cells, relying on the selfassembly capacity of the cells or on the use of preformed or printed ECM. [32][33][34] The adhesion of cells and their homeostasis within the organoids are consolidated by the ECM that allows exchanges between the cells and plays a role in the physical support of the 3D structure.…”

Section: Discussionmentioning

confidence: 99%

Human induced pluripotent stem cells‐derived liver organoids grown on a Biomimesys® hyaluronic acid‐based hydroscaffold as a new model for studying human lipoprotein metabolism

Roudaut,

Caillaud,

Souguir

et al. 2024

Bioengineering & Transla Med

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The liver plays a key role in the metabolism of lipoproteins, controlling both production and catabolism. To accelerate the development of new lipid‐lowering therapies in humans, it is essential to have a relevant in vitro study model available. The current hepatocyte‐like cells (HLCs) models derived from hiPSC can be used to model many genetically driven diseases but require further improvement to better recapitulate the complexity of liver functions. Here, we aimed to improve the maturation of HLCs using a three‐dimensional (3D) approach using Biomimesys®, a hyaluronic acid‐based hydroscaffold in which hiPSCs may directly form aggregates and differentiate toward a functional liver organoid model. After a 28‐day differentiation 3D protocol, we showed that many hepatic genes were upregulated in the 3D model (liver organoids) in comparison with the 2D model (HLCs). Liver organoids, grown on Biomimesys®, exhibited an autonomous cell organization, were composed of different cell types and displayed enhanced cytochromes P450 activities compared to HLCs. Regarding the functional capacities of these organoids, we showed that they were able to accumulate lipids (hepatic steatosis), internalize low‐density lipoprotein and secrete apolipoprotein B. Interestingly, we showed for the first time that this model was also able to produce apolipoprotein (a), the apolipoprotein (a) specific of Lp(a). This innovative hiPSC‐derived liver organoid model may serve as a relevant model for studying human lipopoprotein metabolism, including Lp(a).

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Section: Discussionmentioning

confidence: 99%

Human induced pluripotent stem cells‐derived liver organoids grown on a Biomimesys® hyaluronic acid‐based hydroscaffold as a new model for studying human lipoprotein metabolism

Roudaut,

Caillaud,

Souguir

et al. 2024

Bioengineering & Transla Med

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“…F8) still remained low in hiPSC-derived LSECs, demonstrating incomplete conversion (Gage et al 2020). Heterotypic interactions between LSECs and other liver resident cell types are also important for the maintenance of LSEC identity in vitro, as it has been exemplified in LSEC-hepatocyte co-culture experiments (Gómez-Salinero et al 2022b) and in more complex systems such as organoids and liver-on-a-chip (Rezvani et al 2023). Future work should address the completion of the LSEC model based on the overexpression of TFs described in this review and looking in more detail at the cell-to-cell signalling pathways that contribute to specification of the liver endothelium during embryonic and postnatal development.…”

Section: Future Directionsmentioning

confidence: 96%

RISING STARS: Liver sinusoidal endothelial transcription factors in metabolic homeostasis and disease

Nagy

Maude

Birdsey

et al. 2023

Journal of Molecular Endocrinology

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Liver sinusoidal endothelial cells (LSECs) are highly specialized endothelial cells that form the liver microvasculature. LSECs maintain liver homeostasis, scavenging bloodborne molecules, regulating immune response, and actively promoting hepatic stellate cell quiescence. These diverse functions are underpinned by a suite of unique phenotypical attributes distinct from other blood vessels. In recent years, studies have begun to reveal the specific contributions of LSECs to liver metabolic homeostasis and how LSEC dysfunction associates with disease aetiology. This has been particularly evident in the context of non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of metabolic syndrome, which is associated with loss of key LSEC phenotypical characteristics and molecular identity. Comparative transcriptome studies of LSECs and other endothelial cells, together with rodent knockout models, have revealed that loss of LSEC identity through disruption of core transcription factor activity leads to impaired metabolic homeostasis and to hallmarks of liver disease. This review explores the current knowledge of LSEC transcription factors, covering their roles in LSEC development and maintenance of key phenotypic features, which, when disturbed, lead to loss of liver metabolic homeostasis and promote features of chronic liver diseases, such as non-alcoholic liver disease.

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“…These slices are obtained by cutting fresh liver tissue with a Krumdieck tissue slicer or automated vibratome [167] to thicknesses of as little as 100 µm [168], although the most widely used thickness is 250 µm, generally with a diameter of 5-8 mm. These slices are cultured in regular tissue culture plates in static, dynamic, or bioreactor-based systems [104,167,169,170]. Liver slices are reproducible, cheap, and maintain the viability of hepatocytes, Kupffer, endothelial, and hepatic stellate cells for five days in controlled culture conditions [167,168], and up to 15 days under certain conditions [171].…”

Section: Precision Cut Liver Slicesmentioning

confidence: 99%

NAFLD-Related HCC: Focus on the Latest Relevant Preclinical Models

Fang

Celton-Morizur

2023

Cancers

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Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and one of the deadliest cancers worldwide. Despite extensive research, the biological mechanisms underlying HCC’s development and progression remain only partially understood. Chronic overeating and/or sedentary-lifestyle-associated obesity, which promote Non-Alcoholic Fatty Liver Disease (NAFLD), have recently emerged as worrying risk factors for HCC. NAFLD is characterized by excessive hepatocellular lipid accumulation (steatosis) and affects one quarter of the world’s population. Steatosis progresses in the more severe inflammatory form, Non-Alcoholic Steatohepatitis (NASH), potentially leading to HCC. The incidence of NASH is expected to increase by up to 56% over the next 10 years. Better diagnoses and the establishment of effective treatments for NAFLD and HCC will require improvements in our understanding of the fundamental mechanisms of the disease’s development. This review describes the pathogenesis of NAFLD and the mechanisms underlying the transition from NAFL/NASH to HCC. We also discuss a selection of appropriate preclinical models of NAFLD for research, from cellular models such as liver-on-a-chip models to in vivo models, focusing particularly on mouse models of dietary NAFLD-HCC.

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Modeling Nonalcoholic Fatty Liver Disease in the Dish Using Human-Specific Platforms: Strategies and Limitations

Cited by 8 publications

References 82 publications

Human induced pluripotent stem cells‐derived liver organoids grown on a Biomimesys® hyaluronic acid‐based hydroscaffold as a new model for studying human lipoprotein metabolism

Human induced pluripotent stem cells‐derived liver organoids grown on a Biomimesys® hyaluronic acid‐based hydroscaffold as a new model for studying human lipoprotein metabolism

RISING STARS: Liver sinusoidal endothelial transcription factors in metabolic homeostasis and disease

NAFLD-Related HCC: Focus on the Latest Relevant Preclinical Models

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