Bioengineered Liver Models for Investigating Disease Pathogenesis and Regenerative Medicine

Abstract

Owing to species-specific differences in liver pathways, in vitro human liver models are utilized for elucidating mechanisms underlying disease pathogenesis, drug development, and regenerative medicine. To mitigate limitations with de-differentiated cultures, bioengineers have developed advanced techniques/platforms, including micropatterned cocultures, spheroids/organoids, bioprinting, and microfluidic devices, for perfusing cell cultures and liver slices. Such techniques improve mature functions and culture lifetime of primary and stem-cell human liver cells. Furthermore, bioengineered liver models display several features of liver diseases including infections with pathogens (e.g., malaria, hepatitis C/B viruses, Zika, dengue, yellow fever), alcoholic/nonalcoholic fatty liver disease, and cancer. Here, we discuss features of bioengineered human liver models, their uses for modeling aforementioned diseases, and how such models are being augmented/adapted for fabricating implantable human liver tissues for clinical therapy. Ultimately, continued advances in bioengineered human liver models have the potential to aid the development of novel, safe, and efficacious therapies for liver disease.

Comparison of Wild-Type and High-risk PNPLA3 variants in a Human Biomimetic Liver Microphysiology System for Metabolic Dysfunction-associated Steatotic Liver Disease Precision Therapy

“…MPS are 3D microfluidic platforms composed of multiple cell types that mimic overall organ structure and provide cell-tocell communication using human primary cells, immortalized cell lines, and iPSCs (39)(40)(41). Recently, multiple human liver MPS have evolved and been implemented to study mechanisms of MASLD pathogenesis and serve as drug testing platforms (40,(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60). We have implemented the liver acinus microphysiology system (LAMPS), a structured biomimetic, that is a 3D layered model constructed through a combination of sequential cell layering and cell-to-cell selforganization between 4 key liver cell types including primary hepatocytes and liver sinusoidal endothelial cells (LSECs) as well as cell lines for hepatic stellate cells (the LX-2 cell line) and Kupffer-like cells (THP-1 cell line), and maintained under flow to mimic either Zone 1 or Zone 3 oxygen tensions (61)(62)(63) Our overall strategy towards implementing a precision medicine platform for MASLD has been to first test the MASLD LAMPS model with key primary cells as a benchmark for the next phase using "patient biomimetic twins" (PBTs) produced using patient, induced pluripotent stem cells (iPSCs) (40) (Fig 1A).…”

Human organoids-on-chips for biomedical research and applications

“…In this study, Wang et al assessed the changes in the glomerular barrier in phenotypic expression, reactive oxidative stress and barrier integrity under pathological conditions 254 . In addition to common metabolic and progressive diseases, hiPSC-derived organoids as an ideal cell source have been exploited to model infectious, genetic and nutritional diseases and so on 255 . These models can be used to assess short-term or long-term effects of drugs/stimuli on specific tissues/organs.…”

Advancements in MAFLD Modeling with Human Cell and Organoid Models

“…The vascular system is essential for modeling multiple MAFLD features ( Figure 2 A and Figure 3 A), including immune cell migration in the liver sinusoid during inflammation and fibrogenesis. Bioengineering techniques are often employed in recreating such a vascular system which is also crucial for supplementing nutrients to cells in the core of large 3D cellular models [ 166 , 167 , 168 , 169 ]. In addition, bioengineering techniques are also often engaged to achieve the precision placement of cells in a multi-cellular model.…”