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Image-Based High-Content Analysis, Stem Cells and Nanomedicines: A Novel Strategy for Drug Discovery
Published in Dan Peer, Handbook of Harnessing Biomaterials in Nanomedicine, 2021
Leonardo J. Solmesky, Yonatan Adalist, Miguel Weil
Since hepatotoxicity is one of the major reasons for drug non-approval, the development of an assay predictive of drug-induced liver toxicity has been considered imperative. Individual conventional assays in animals have not been reliable in predicting human hepatotoxicity. However, when cellular assays are used in combination, as it is possible using the HCS approach, the level of hepatotoxicity prediction is improved for these assays (e.g., mitochondrial activity, glutathione and cell proliferation). Furthermore, the predictive value can be dramatically increased in HCS assays that use human hepatocyte cell lines. Thus, the assessment of multiple pre-lethal hepatotoxic effects of a potential drug on individual live cells, including mitochondrial toxicity, oxidative stress, deregulation of calcium homeostasis, phospholipidosis, apoptosis, and antiproliferative effects, can be well predicted [64].
Toxic Responses of the Liver
Published in Stephen K. Hall, Joana Chakraborty, Randall J. Ruch, Chemical Exposure and Toxic Responses, 2020
The liver can be organized into subunits based upon its anatomy or its functions. The anatomical structural subunit is the liver lobule which is simply a hexagon that has a portal triad at each corner and the central vein at the center (Figure 8.1). The portal triad contains branches of the portal vein and hepatic artery and a bile duct. This latter structure carries bile to the gall bladder as described below. The central vein drains blood into the hepatic vein for exit from the liver. Blood flows from the hepatic artery and portal vein branches in the portal triad, mixes in the penetrating vessels, then flows between the plates of hepatic parenchymal cells (hepatocytes) to the central vein. Hepatocytes perform most metabolic functions of the liver. Injury to hepatocytes can be classified anatomically in this scheme as periportal (around the portal triad), midzonal, or pericentral (around the central venule).
Recent Advances of Alginate Biomaterials in Tissue Engineering
Published in Shakeel Ahmed, Aisverya Soundararajan, Marine Polysaccharides, 2018
Jayachandran Venkatesan, Sukumaran Anil, Sandeep Kumar Singh, Se-Kwon Kim
Liver diseases are one the prime reason responsible for human deaths and are increasing at an alarming rate, with a million deaths per year. In addition, the waiting period for liver transplantation is also increasing due to shortage of organs. Therefore, to meet the huge demand for the liver, liver tissue engineering is one of the best ways to overcome this issue. Materials and cells from the liver tissue are often considered to develop the liver. The problem exists in limited availability of cells, cells from diseased organs and lack of in vitro propagation. However, great progress has been made in stem cell differentiation towards hepatocytes and use for liver tissue engineering [101–104]. Kumari et al. (2016) developed a poly(ethylene glycol)-alginate cryogel matrix for in vitro culture for human liver cells [105]. Alginate spherical microcarriers were modified with microparticles of de-cellularised liver tissue [106]. Also alginate-chitosan microcapsules for hepatocyte culture were developed recently [107].
Decellularized liver matrix-modified chitosan fibrous scaffold as a substrate for C3A hepatocyte culture
Published in Journal of Biomaterials Science, Polymer Edition, 2020
Chaochen Zhao, Yang Li, Gongze Peng, Xiongxin Lei, Guifeng Zhang, Yi Gao
Culturing hepatocytes is difficult in vitro, because of dedifferentiation and loss of liver-specific functions, like albumin secretion and urea synthesis [32]. In recent years, individual ECM constituents have been used as a scaffold material for hepatocyte culture, in which hepatocyte adhesion and hepatocyte-specific functions can be enhanced in a short time. However, these scaffolds cannot prevent hepatocytes dedifferentiation [12]. ECM of each organ stems from the resident cells and should logically be the optimum scaffold material. In view of that, it is not surprising that liver-derived ECM is appropriate for hepatocytes culture. Many studies have proved that ECM scaffolds were superior to scaffolds composed of a single constituent (such as type-1 collagen), in that the former can guarantee hepatocyte differentiation and hepatocyte-specific functions for a longer time [33, 34].
A review of hepatic nanotoxicology – summation of recent findings and considerations for the next generation of study designs
Published in Journal of Toxicology and Environmental Health, Part B, 2020
Ali Kermanizadeh, Leagh G Powell, Vicki Stone
For this reason, it is highly recommended that KCs are incorporated in next generation in vitro hepatic models intended for hazard assessment. This is even more imperative if the in vitro models are intended for utilization as a surrogate for in vivo testing (Kermanizadeh et al. 2019a, 2019b). The use of in vitro hepatocyte models has been beneficial for the last three decades in research and various application areas. Traditionally, hepatocytes were considered as the most important cell population in the liver for drugs and chemical toxicity screening. This is logical and understandable as drugs and chemical toxicity is mainly dominated by their metabolism, with the metabolic intermediates often being hepatotoxic. However, since bio-persistent NMs are not necessarily metabolized, but rather first interact and/are internalized by KCs (Aalapati et al. 2014; Shrivastava et al. 2014), the use of hepatocyte only mono-cultures might not be appropriate for particle hepatic toxicity screening. It is also important to consider that numerous investigators demonstrated that only a small proportion of the administered dose of any bio-persistent material reaches the hepatocytes in vivo (Sepehri et al. 2017; Wen et al. 2015). From these data, it is clear that KCs are highly involved both in NM-induced hepatic biological responses and in their accumulation.
Genetic toxicity assessment using liver cell models: past, present, and future
Published in Journal of Toxicology and Environmental Health, Part B, 2020
Xiaoqing Guo, Ji-Eun Seo, Xilin Li, Nan Mei
Liver is the primary organ for chemical metabolism and a target of many toxicants. Human hepatocytes are frequently employed for testing drug-induced liver injury due to their metabolic competence. Recently, hepatocytes have been increasingly proposed as an in vitro model for genotoxicity assessment. This review article summarizes the past and recent studies that utilize liver cell models, including primary hepatocytes, hepatoma cells, fetal hepatocytes, engineered hepatocytes, hepatocytes derived from stem cells, as well as 3 dimensional (3D) hepatocyte spheroids, for various standard genotoxicity assays including the MN assay, Comet assay, mutation assays, as well as some recently developed promising assays, with the aim of providing scientific data to evaluate the appropriateness of hepatocytes for genotoxicity testing.