Abstract
The liver is the most important metabolic hub of endo and xenobiotic compounds. Pre-clinical studies using rodents to evaluate the toxicity of new drugs and cosmetics may produce inconclusive results for predicting clinical outcomes in humans, moreover being banned in the European Union. Human liver modeling using primary hepatocytes presents low reproducibility due to batch-to-batch variability, while iPSC-derived hepatocytes in monolayer cultures (2D) show reduced cellular functionality. Here we review the current status of the two most robust in vitro approaches in improving hepatocyte phenotype and metabolism while mimicking the hepatic physiological microenvironment: organoids and liver-on-chip. Both technologies are reviewed in design and manufacturing techniques, following cellular composition and functionality. Furthermore, drug screening and liver diseases modeling efficiencies are summarized. Finally, organoid and liver-on-chip technologies are compared regarding advantages and limitations, aiming to guide the selection of appropriate models for translational research and the development of such technologies.
Highlights
The liver is the largest solid organ in the human body with a highlighted capacity of regeneration, acting distinctively as a regulator of blood sugar and ammonia levels, a synthetic hub of hormones, plasma proteins, and bile, a storage center of iron and vitamins as well as a main metabolizer of endogenous and exogenous compounds (Boeri et al, 2019).Two million deaths per year worldwide are associated with liver diseases, which are triggered by environmental cues (Ehrlich et al, 2019)
The liver comprises a combination of resident parenchymal cells and nonparenchymal cells (NPCs), such as cholangiocytes, hepatic stellate cells (HSCs), Kupffer cells, and liver sinusoidal endothelial cells (LSECs) (Guo et al, 2011) (Figure 2)
As the main component of the liver, representing 80% of the organ mass (Godoy et al, 2013), hepatocytes are responsible for the metabolism of endogenous and exogenous molecules (Usta et al, 2015) mediated by cytochrome P450 (CYP450) enzymes (Deng et al, 2019)
Summary
The liver is the largest solid organ in the human body with a highlighted capacity of regeneration, acting distinctively as a regulator of blood sugar and ammonia levels, a synthetic hub of hormones, plasma proteins (e.g., albumin, fibrinogen and transferrin), and bile, a storage center of iron and vitamins as well as a main metabolizer of endogenous and exogenous compounds (Boeri et al, 2019). Hepatitis B and C are the major causes of viral liver disease, affecting over 71 million people in 2019 as estimated by the WHO, higher numbers than HIV-related cases (Kulkeaw and Pengsart, 2021). The development of new drugs by the pharmaceutical industry takes approximately a decade, with estimated one in 5000 drug candidates completing the journey. This inefficiency is due to identification of cardiac toxicity and, most frequently, druginduced liver injury (DILI) (Skardal et al, 2020). We discuss the applications and limitations of current in vitro models and how organoid and liver-on-a-chip technologies leverage liver function studies, disease modeling, and new drugs evaluation (Figure 1)
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