Modeling alcohol-associated liver disease in a human Liver-Chip

Nawroth, Janna; Petropolis, Debora B.; Manatakis, Dimitris V.; Maulana, Tengku Ibrahim; Burchett, G; Schlünder, Katharina; Witt, Anke; Shukla, Abhishek; Kodella, Konstantia; Ronxhi, Janey; Kulkarni, Gauri; Hamilton, Geraldine A.; Seki, Ekihiro; Lu, Shelly C.; Karalis, Katia

doi:10.1016/j.celrep.2021.109393

Cited by 49 publications

(38 citation statements)

References 105 publications

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“…The next day, the gel was then flushed twice with 100 µL of warm medium at 187.5 µL/s flow (Eppendorf Xplorer automatic pipet; Eppendorf). This generated a 3D-ECM layer on the membrane with a thickness of 20-85 µm, as optimized previously 37 (Supplementary Figure 2a and b). To assess and confirm ECM scaffold formation of different ECM compositions, we stained the gels with a fluorescent dye.…”

Section: Methodsmentioning

confidence: 99%

Breathing on Chip: Dynamic flow and stretch tune cellular composition and accelerate mucociliary maturation of airway epitheliumin vitro

Nawroth

Roth

Schadewijk

et al. 2021

Preprint

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Human lung function is intricately linked to the mechanics of breathing; however, it remains unknown whether and how these mechanical cues shape human lung cellular biology. While respiration-related strains and fluid flows have been suggested to promote alveolar epithelial cell function, the study of such fundamental mechanisms in the conducting airway epithelium has been hindered by the lack of suitable in vitro airway models. Here, we developed a model of human bronchial airway epithelium using well-differentiated primary cell cultures on a commercial Organs-on-Chips platform that enables the application of breathing-associated airflow and cyclic strain. It furthermore features optional endothelial cell co-culture to allow for crosstalk with the vascular compartment. Using this model, we evaluated the impact of airflow and physiological levels of cyclic strain on airway epithelial cell differentiation and function. Our findings suggest that breathing-associated mechanical stimulation changes epithelial composition, reduces secretion of IL-8, and downregulates gene expression of matrix metalloproteinase 9, fibronectin, and other extracellular matrix (ECM) factors. These results indicate that breathing-associated forces are important modulators of airway epithelial cell biology and that their fine-tuned application could generate models of specific epithelial phenotypes and pathologies.

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Section: Methodsmentioning

confidence: 99%

Breathing on Chip: Dynamic flow and stretch tune cellular composition and accelerate mucociliary maturation of airway epitheliumin vitro

Nawroth

Roth

Schadewijk

et al. 2021

Preprint

Self Cite

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“…According to many scholars, one of the early indicators of liver function decrease is an alteration of bile canaliculi. In a study by Nawroth et al, the ECM scaffolding was conducted to improve the integrity of bile canaliculi structure, which further allowed to track alteration in canaliculi network in response to alcohol exposure in microfluidic devices as shown in Figure 3 A (2021) [ 67 ]. As a result, in response to alcohol, the expansion and decreased branching of bile canaliculi was observed, which goes along with the currency of ALD in humans with signs of cholestasis or decreased bile flow.…”

Section: Liver-on-a-chip Platforms Modeling Aldmentioning

confidence: 99%

“… Modeling Alcoholic Liver Disease using microfluidic devices. ( A ) ALD Liver-Chip model with approach of exposing to alcohol [ 67 ] (reproduced with permission from Nawroth et al, 2020 Copyright: Cell Reports 36, 109393, July 20, 2021). ( B ) ALD model prepared by culturing primary hepatocytes with stellate cells in PDMS based Liver-on-Chip [ 68 ] (reproduced with permission from Lee et al, 2016).…”

Section: Figurementioning

confidence: 99%

Microfluidic Organ-on-a-Chip Devices for Liver Disease Modeling In Vitro

2022

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Mortality from liver disease conditions continues to be very high. As liver diseases manifest and progress silently, prompt measures after diagnosis are essential in the treatment of these conditions. Microfluidic organs-on-chip platforms have significant potential for the study of the pathophysiology of liver diseases in vitro. Different liver-on-a-chip microphysiological platforms have been reported to study cell-signaling pathways such as those activating stellate cells within liver diseases. Moreover, the drug efficacy for liver conditions might be evaluated on a cellular metabolic level. Here, we present a comprehensive review of microphysiological platforms used for modelling liver diseases. First, we briefly introduce the concept and importance of organs-on-a-chip in studying liver diseases in vitro, reflecting on existing reviews of healthy liver-on-a-chip platforms. Second, the techniques of cell cultures used in the microfluidic devices, including 2D, 3D, and spheroid cells, are explained. Next, the types of liver diseases (NAFLD, ALD, hepatitis infections, and drug injury) on-chip are explained for a further comprehensive overview of the design and methods of developing liver diseases in vitro. Finally, some challenges in design and existing solutions to them are reviewed

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“…A major limitation of the above models is that several NAFLD-associated organs such as the pancreas, white adipose tissue and kidney are neglected. To address this, previously established OoC modules integrating adipose [ 83 ], pancreatic [ 84 ], kidney tissue [ 85 ] and hepatic tissue [ 86 ] could be linked together. Thus far, organ cross-talk via bacterial metabolites, exosomes, miRNA etc.…”

Section: Applications Of Metabolism-focused Multi-organ Chipsmentioning

confidence: 99%

Studying metabolism with multi-organ chips: new tools for disease modelling, pharmacokinetics and pharmacodynamics

et al. 2022

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Non-clinical models to study metabolism including animal models and cell assays are often limited in terms of species translatability and predictability of human biology. This field urgently requires a push towards more physiologically accurate recapitulations of drug interactions and disease progression in the body. Organ-on-chip systems, specifically multi-organ chips (MOCs), are an emerging technology that is well suited to providing a species-specific platform to study the various types of metabolism (glucose, lipid, protein and drug) by recreating organ-level function. This review provides a resource for scientists aiming to study human metabolism by providing an overview of MOCs recapitulating aspects of metabolism, by addressing the technical aspects of MOC development and by providing guidelines for correlation with in silico models. The current state and challenges are presented for two application areas: (i) disease modelling and (ii) pharmacokinetics/pharmacodynamics. Additionally, the guidelines to integrate the MOC data into in silico models could strengthen the predictive power of the technology. Finally, the translational aspects of metabolizing MOCs are addressed, including adoption for personalized medicine and prospects for the clinic. Predictive MOCs could enable a significantly reduced dependence on animal models and open doors towards economical non-clinical testing and understanding of disease mechanisms.

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Modeling alcohol-associated liver disease in a human Liver-Chip

Cited by 49 publications

References 105 publications

Breathing on Chip: Dynamic flow and stretch tune cellular composition and accelerate mucociliary maturation of airway epitheliumin vitro

Breathing on Chip: Dynamic flow and stretch tune cellular composition and accelerate mucociliary maturation of airway epitheliumin vitro

Microfluidic Organ-on-a-Chip Devices for Liver Disease Modeling In Vitro

Studying metabolism with multi-organ chips: new tools for disease modelling, pharmacokinetics and pharmacodynamics

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