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"Liver-on-a-Chip" Cultures of Primary Hepatocytes and Kupffer Cells for Hepatitis B Virus Infection
Published on: February 19, 2019
Human Liver Infection in a Dish: Easy-To-Build 3D Liver Models for Studying Microbial Infection
Debora B Petropolis1,2, Daniela M Faust1, Matthieu Tolle1
1Cell Biology of Parasitism Unit, Inserm U786, BCI, Institut Pasteur, Paris, France.
Abstract:
Human liver infection is a major cause of death worldwide, but fundamental studies on infectious diseases affecting humans have been hampered by the lack of robust experimental models that accurately reproduce pathogen-host interactions in an environment relevant for the human disease. In the case of liver infection, one consequence of this absence of relevant models is a lack of understanding of how pathogens cross the sinusoidal endothelial barrier and parenchyma. To fill that gap we elaborated human 3D liver in vitro models, composed of human liver sinusoidal endothelial cells (LSEC) and Huh-7 hepatoma cells as hepatocyte model, layered in a structure mimicking the hepatic sinusoid, which enable studies of key features of early steps of hepatic infection. Built with established cell lines and scaffold, these models provide a reproducible and easy-to-build cell culture approach of reduced complexity compared to animal models, while preserving higher physiological relevance compared to standard 2D systems. For proof-of-principle we challenged the models with two hepatotropic pathogens: the parasitic amoeba Entamoeba histolytica and hepatitis B virus (HBV). We constructed four distinct setups dedicated to investigating specific aspects of hepatic invasion: 1) pathogen 3D migration towards hepatocytes, 2) hepatocyte barrier crossing, 3) LSEC and subsequent hepatocyte crossing, and 4) quantification of human hepatic virus replication (HBV). Our methods comprise automated quantification of E. histolytica migration and hepatic cells layer crossing in the 3D liver models. Moreover, replication of HBV virus occurs in our virus infection 3D liver model, indicating that routine in vitro assays using HBV or others viruses can be performed in this easy-to-build but more physiological hepatic environment. These results illustrate that our new 3D liver infection models are simple but effective, enabling new investigations on infectious disease mechanisms. The better understanding of these mechanisms in a human-relevant environment could aid the discovery of drugs against pathogenic liver infection.
Insights
Researchers developed a novel 3D human liver model to study infections. This model accurately mimics pathogen interactions, aiding the understanding of liver disease mechanisms and drug discovery for infectious diseases.
Area of Science:
- * Infectious diseases and hepatology.
- * Development of advanced in vitro models for human physiology.
Background:
- * Human liver infections are a significant global health concern, yet research is limited by a lack of accurate experimental models.
- * Understanding how pathogens invade the liver, specifically crossing the sinusoidal endothelial and parenchymal barriers, remains a challenge.
- * Existing models often lack the physiological relevance needed to study complex pathogen-host interactions in the liver.
Purpose of the Study:
- * To create and validate a novel 3D human liver in vitro model for studying hepatic infections.
- * To investigate the early steps of liver invasion by hepatotropic pathogens.
- * To provide a more physiologically relevant platform for studying infectious disease mechanisms and facilitating drug discovery.
Main Methods:
- * Construction of a 3D human liver model using human liver sinusoidal endothelial cells (LSEC) and Huh-7 hepatoma cells, mimicking the hepatic sinusoid structure.
- * Development of four distinct experimental setups to study pathogen migration, barrier crossing, and viral replication within the 3D model.
- * Utilized automated quantification for analyzing pathogen migration and cell layer crossing, and assessed hepatitis B virus (HBV) replication.
Main Results:
- * The 3D liver model successfully replicated key aspects of early hepatic infection, including pathogen migration and barrier penetration.
- * Demonstrated the invasion of the 3D liver model by the parasitic amoeba Entamoeba histolytica.
- * Confirmed the replication of hepatitis B virus (HBV) within the developed 3D model, validating its utility for virological studies.
Conclusions:
- * The developed 3D human liver infection model offers a reproducible, simplified, yet physiologically relevant alternative to animal models and 2D systems.
- * This model enables detailed investigation into the mechanisms of liver infections by various pathogens.
- * The findings support the potential of this model for advancing research on infectious liver diseases and accelerating the development of new therapeutic strategies.
