Bioengineered Liver Cell Models of Hepatotropic Infections

Paula M. Alves,Catarina Brito,Ana F. Rodrigues,Francisca Arez

doi:10.3390/v13050773

Paula M. Alves, Catarina Brito + Show 2 more

Open Access

https://doi.org/10.3390/v13050773

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Abstract

Hepatitis viruses and liver-stage malaria are within the liver infections causing higher morbidity and mortality rates worldwide. The highly restricted tropism of the major human hepatotropic pathogens—namely, the human hepatitis B and C viruses and the Plasmodium falciparum and Plasmodium vivax parasites—has hampered the development of disease models. These models are crucial for uncovering the molecular mechanisms underlying the biology of infection and governing host–pathogen interaction, as well as for fostering drug development. Bioengineered cell models better recapitulate the human liver microenvironment and extend hepatocyte viability and phenotype in vitro, when compared with conventional two-dimensional cell models. In this article, we review the bioengineering tools employed in the development of hepatic cell models for studying infection, with an emphasis on 3D cell culture strategies, and discuss how those tools contributed to the level of recapitulation attained in the different model layouts. Examples of host–pathogen interactions uncovered by engineered liver models and their usefulness in drug development are also presented. Finally, we address the current bottlenecks, trends, and prospect toward cell models’ reliability, robustness, and reproducibility.

Highlights

The liver as a critical role in the metabolism and clearance of toxins and pathogens.It is a highly complex organ, composed of cell types of different origins, which during development arise from different germ layers: the liver sinusoidal endothelial cells (LSECs), hepatic stellate cells, and Kupffer cells
The liver microenvironment induces immune tolerance to antigens presented by non-parenchymal liver cells or expressed by hepatocytes and directly presented on major histocompatibility complex (MHC) molecules
Viral hepatitides are a group of liver diseases caused by one of five known hepatitis viruses: hepatitis A virus (HAV) to hepatitis E virus (HEV) (Table 1)

Summary

Introduction

The liver as a critical role in the metabolism and clearance of toxins and pathogens It is a highly complex organ, composed of cell types of different origins, which during development arise from different germ layers: the liver sinusoidal endothelial cells (LSECs), hepatic stellate cells, and Kupffer cells. The liver microenvironment induces immune tolerance to antigens presented by non-parenchymal liver cells or expressed by hepatocytes and directly presented on major histocompatibility complex (MHC) molecules. Infectious liver diseases have been studied mainly in animal models and hepatic cell lines, focusing on host–pathogen interactions. These models contributed to important knowledge on pathogens’ biology and drug response. We further discuss the advantages and drawbacks of these models, the levels of recapitulation of disease, and their suitability for addressing specific scientific questions, as well as their levels of reliability, robustness, and reproducibility

Hepatitis Viruses

Plasmodium

Experimental Models of Liver Infection

Animal Models

Bioengineered Liver Cell Models

Scaffold-Based 3D Cultures

Scaffold-Free 3D Cultures

Findings

Methods