Department of Biomedical Engineering, University of Miami, Coral Gables, Florida.
Department of Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Miami, Florida.
Semin Liver Dis. 2023 Feb;43(1):31-49. doi: 10.1055/a-1981-5944. Epub 2022 Nov 19.
Viral hepatitis is a leading cause of liver morbidity and mortality globally. The mechanisms underlying acute infection and clearance, versus the development of chronic infection, are poorly understood. In vitro models of viral hepatitis circumvent the high costs and ethical considerations of animal models, which also translate poorly to studying the human-specific hepatitis viruses. However, significant challenges are associated with modeling long-term infection in vitro. Differentiated hepatocytes are best able to sustain chronic viral hepatitis infection, but standard two-dimensional models are limited because they fail to mimic the architecture and cellular microenvironment of the liver, and cannot maintain a differentiated hepatocyte phenotype over extended periods. Alternatively, physiomimetic models facilitate important interactions between hepatocytes and their microenvironment by incorporating liver-specific environmental factors such as three-dimensional ECM interactions and co-culture with non-parenchymal cells. These physiologically relevant interactions help maintain a functional hepatocyte phenotype that is critical for sustaining viral hepatitis infection. In this review, we provide an overview of distinct, novel, and innovative in vitro liver models and discuss their functionality and relevance in modeling viral hepatitis. These platforms may provide novel insight into mechanisms that regulate viral clearance versus progression to chronic infections that can drive subsequent liver disease.
病毒性肝炎是全球导致肝脏发病率和死亡率的主要原因。急性感染和清除与慢性感染发展的机制尚未被充分理解。病毒性肝炎的体外模型规避了动物模型的高成本和伦理问题，这些模型也很难转化为研究人类特异性肝炎病毒。然而，体外长期感染建模仍然存在重大挑战。分化的肝细胞最能维持慢性病毒性肝炎感染，但标准的二维模型受到限制，因为它们无法模拟肝脏的结构和细胞微环境，并且无法在较长时间内维持分化的肝细胞表型。相反，生理模型通过纳入肝特异性环境因素，如三维细胞外基质相互作用和与非实质细胞的共培养，促进了肝细胞及其微环境之间的重要相互作用。这些生理相关的相互作用有助于维持功能性肝细胞表型，这对于维持病毒性肝炎感染至关重要。在这篇综述中，我们概述了不同的、新颖的和创新的体外肝脏模型，并讨论了它们在模拟病毒性肝炎方面的功能和相关性。这些平台可能为调节病毒清除与进展为慢性感染的机制提供新的见解，从而导致随后的肝脏疾病。
