Modelling T-cell immunity against hepatitis C virus with liver organoids in a microfluidic coculture system

Natarajan, Vaishaali; Simoneau, Camille R.; Erickson, Ann L.; Meyers, Nathan L.; Baron, Jody L.; Cooper, Stewart; McDevitt, Todd C.; Ott, Melanie

doi:10.1098/rsob.210320

Cited by 31 publications

(19 citation statements)

References 32 publications

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“…They used this co-culture platform to study the adaptive immune response in the context of HCV infection, and were able to recapitulate a more physiological interaction between infected hepatic organoids and T cells, by introducing T cells into the perfused media and allowing them to encounter the infected organoids independently. 127 This study highlights the utility of physiomimetic systems as more physiological models of the adaptive immune response.…”

Section: Physiomimetic Models To Study Viral Infectionmentioning

confidence: 88%

“…As an HCV model, Natarajan et al infected primary liver organoids encapsulated in basement membrane matrix with HCV, and perfused the cells in co-culture with T cells on a commercially available chip, idenTx, from AIM Biotech. They used this co-culture platform to study the adaptive immune response in the context of HCV infection, and were able to recapitulate a more physiological interaction between infected hepatic organoids and T cells, by introducing T cells into the perfused media and allowing them to encounter the infected organoids independently (127). This study highlights the utility of physiomimetic systems as more physiological models of the adaptive immune response.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

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Physiomimetic In Vitro Human Models for Viral Infection in the Liver

et al. 2022

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Viral hepatitis is a leading cause of liver morbidity and mortality globally. The mechanisms underlying acute infection and clearance, versus the development of chronic infection, are poorly understood. In vitro models of viral hepatitis circumvent the high costs and ethical considerations of animal models, which also translate poorly to studying the human-specific hepatitis viruses. However, significant challenges are associated with modeling long-term infection in vitro. Differentiated hepatocytes are best able to sustain chronic viral hepatitis infection, but standard two-dimensional (2D) models are limited because they fail to mimic the architecture and cellular microenvironment of the liver, and cannot maintain a differentiated hepatocyte phenotype over extended periods. Alternatively, physiomimetic models facilitate important interactions between hepatocytes and their microenvironment by incorporating liver-specific environmental factors such as three-dimensional (3D) ECM interactions and co-culture with non-parenchymal cells. These physiologically relevant interactions help maintain a functional hepatocyte phenotype that is critical for sustaining viral hepatitis infection. In this review, we provide an overview of distinct, novel, and innovative in vitro liver models and discuss their functionality and relevance in modeling viral hepatitis. These platforms may provide novel insight into mechanisms that regulate viral clearance versus progression to chronic infections that can drive subsequent liver disease.

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Section: Physiomimetic Models To Study Viral Infectionmentioning

confidence: 88%

Section: Accepted Manuscriptmentioning

confidence: 99%

Physiomimetic In Vitro Human Models for Viral Infection in the Liver

et al. 2022

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“…The majority of scaffold-based chips use pre-formed 3D hydrogel cultures that subsequently introduce perfusion across the surface of the hydrogel structure ( Bavli et al, 2016 ; Schepers et al, 2016 ; Aeby et al, 2018 ; Christoffersson et al, 2018 ; Yajima et al, 2018 ). Natarajan et al (2022) modeled HCV infection in liver organoids encapsulated in basement membrane matrix and perfused on a commercially available chip, idenTx, from AIM Biotech ( Natarajan et al, 2022 ). Alternatively, commercial supplier Hesperos utilized a nylon scaffold to separate cell types in their dual channel platform ( Esch et al, 2015 ).…”

Section: Physiologically Relevant Liver Technologies and Their Applic...mentioning

confidence: 99%

Physiologically relevant microsystems to study viral infection in the human liver

et al. 2022

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Viral hepatitis is a leading cause of liver disease and mortality. Infection can occur acutely or chronically, but the mechanisms that govern the clearance of virus or lack thereof are poorly understood and merit further investigation. Though cures for viral hepatitis have been developed, they are expensive, not readily accessible in vulnerable populations and some patients may remain at an increased risk of developing hepatocellular carcinoma (HCC) even after viral clearance. To sustain infection in vitro, hepatocytes must be fully mature and remain in a differentiated state. However, primary hepatocytes rapidly dedifferentiate in conventional 2D in vitro platforms. Physiologically relevant or physiomimetic microsystems, are increasingly popular alternatives to traditional two-dimensional (2D) monocultures for in vitro studies. Physiomimetic systems reconstruct and incorporate elements of the native cellular microenvironment to improve biologic functionality in vitro. Multiple elements contribute to these models including ancillary tissue architecture, cell co-cultures, matrix proteins, chemical gradients and mechanical forces that contribute to increased viability, longevity and physiologic function for the tissue of interest. These microsystems are used in a wide variety of applications to study biological phenomena. Here, we explore the use of physiomimetic microsystems as tools for studying viral hepatitis infection in the liver and how the design of these platforms is tailored for enhanced investigation of the viral lifecycle when compared to conventional 2D cell culture models. Although liver-based physiomimetic microsystems are typically applied in the context of drug studies, the platforms developed for drug discovery purposes offer a solid foundation to support studies on viral hepatitis. Physiomimetic platforms may help prolong hepatocyte functionality in order to sustain chronic viral hepatitis infection in vitro for studying virus-host interactions for prolonged periods.

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“…co‐cultured liver organoids with CD + T cells in a microfluidic chip to model critical cellular features of hepatitis C virus immunity. [ 180 ] In summary, studies indicate that biomimetic microfluidics dynamics, such as radial flow, perfusion flow, and shear stress as well as molecular and oxygen gradients are essential dynamic cues for mimicking and maintaining liver homeostasis.…”

Section: Modeling Organoid Systems By Applying Microfluidic Techniquesmentioning

confidence: 99%

Microfluidic Techniques for Next‐Generation Organoid Systems

Gong

Kang

et al. 2022

Adv Materials Inter

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PSCs (iPSCs) and embryonic stem cells (ESCs), or adult stem cells (ASCs). Pioneered in the Yoshiki Sasai lab, where cortical tissues and optic-cuplike structures were firstly induced from ESCs in vitro, [1,2] organoid technology is regarded as a milestone in the stem cell field because it cast light upon the path to stably growing self-aggregating and selfrenewing stem cells into native tissues by mimicking developmental processes. [3] Subsequently, the rapidly developing field of organoid technology is advancing the maturity of technology for developing 3D macrostructures of organs such as the retina, [4] heart, [5] liver, [6] kidney, [7] and intestines. [8] In marked contrast to traditional 2D monocultures of cell lines losing cell-cell and cell-matrix interactions, organoids maintain and define in situ phenotypes fairly well. Despite organoids having shown great progress in tissue morphogenesis and organogenesis, the lack of organ-specific biochemical and physical microenvironments and nonphysiological shape and size have limited the function and real-life applications of organoids. Therefore, innovative strategies are urgently needed to precisely control perfusion conditions, nutrient supply, and mechanical cues in order to establish an optimal microenvironment for organoid cultures.The recently developed organs-on-a-chip (OOC) technology provides an in vivo-like microenvironment, showing great potential to enhance our understanding of organ development, physiology, and pathology. [9] Besides, the application of dynamic flow conditions or mechanical stimuli provided by OOCs can improve the terminal maturation of cells. [10,11] OOCs usually are comprised of specialized cell types and tissue elements (biochemical and biophysical cues of in vivo microenvironment), aiming to capture key functions of a specific organ. [12] Organoids rely on the self-organization of growing stem cell aggregates, whereas OOC is based on a reductionist engineering approach. In addition, organoids are multicellular 3D tissue with an architecture resembling some aspects of original tissues, which are not classified as OOC because of their production through stochastic self-organization from PSCs or ASCs and lack of microenvironment elements. [13] However, organoid and OOC techniques each have their own advantages, and they can be appropriately combined to enable highfidelity human modeling from stem cells. [14] Such synergistic Organoids are 3D multicellular structures derived from pluripotent stem cells (PSCs) or adult stem cells (ASCs), which have attracted increasing interest in the fields of drug screening, cell therapy, and regenerative medicine. Despite considerable success in culturing organoids with native microanatomy, challenges to achieving a physiologically relevant microenvironment remain. Complex dynamic feedback between cells and the extracellular matrix and uncontrollable mechano-physiological cues hamper the further study of organoid systems. Innovative engineering approaches are needed to produce, control, and analy...

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Modelling T-cell immunity against hepatitis C virus with liver organoids in a microfluidic coculture system

Cited by 31 publications

References 32 publications

Physiomimetic In Vitro Human Models for Viral Infection in the Liver

Physiomimetic In Vitro Human Models for Viral Infection in the Liver

Physiologically relevant microsystems to study viral infection in the human liver

Microfluidic Techniques for Next‐Generation Organoid Systems

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