In Vitro Models for the Study of Liver Biology and Diseases: Advances and Limitations

Abstract

In vitro models of liver (patho)physiology, new technologies, and experimental approaches are progressing rapidly. Based on cell lines, induced pluripotent stem cells or primary cells derived from mouse or human liver as well as whole tissue (slices), such in vitro single- and multicellular models, including complex microfluidic organ-on-a-chip systems, provide tools to functionally understand mechanisms of liver health and disease. The International Society of Hepatic Sinusoidal Research (ISHSR) commissioned this working group to review the currently available in vitro liver models and describe the advantages and disadvantages of each in the context of evaluating their use for the study of liver functionality, disease modeling, therapeutic discovery, and clinical applicability.

Keywords: Bioengineering; Cirrhosis; Hepatic Sinusoid; Mechanobiology; NAFLD; NASH; Omics.

Figure 1

Schematic view of mostly used in vitro models in hepatology. +, low; ++, medium; +++, high.

Figure 2

Fromsingle cells to liver-on-a-chip and body on-a-chip.

Figure 3

Schematic overview of in vitro and ex vivo liver models using (A) natural scaffolds including hydrogels, fiber-like structures generated by electrospinning, or bioinks, and (B) synthetic scaffolds such as microporous, 3D fibrous, or bioengineered platforms to generate (C) organoids/spheroids, (D) PCLS and bioreactors, and (E) 3D liver sinusoid on a chip. Natural scaffolds obtained from hepatic tissues from various sources such as human, porcine, and rat undergo decellularization using detergents. Synthetic scaffolds including polymer and hydrogel based in combination with novel methods such as 3D printing provides the capability for tuning the properties of the material to re-create the liver microenvironment at stages of disease progression. Current 2D and 3D hepatic models include organoids and spheroids, tissue-based approaches such as PCLS and ex vivo bioreactors, and liver-on-a-chip micropatterned co-culture models. BEASTS, Bio-Engineered Adhesive Siloxane substrate with Tunable Stiffness; ECM, extracellular matrix.