Three-Dimensional Spheroids With Primary Human Liver Cells and Differential Roles of Kupffer Cells in Drug-Induced Liver Injury

Li, Feng; Cao, Li; Parikh, Sonia; Zuo, Rongjun

doi:10.1016/j.xphs.2020.02.021

Cited by 48 publications

(58 citation statements)

References 39 publications

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“…Other cell types used in combination with hepatocytes to establish in-vitro liver models include the non-parenchymal cell types found in the liver (i.e., Kupffer cells, stellate cells, liver sinusoidal endothelial cells (LSECs), and cholangiocytes), with the aim of recapitulating the liver's multi-cellular environment and paracrine signaling. Similar to PHHs, NPCs can be primary human cells derived from liver resection/biopsies (e.g., NPC liver fractions or isolated Kupffer cells) (32,68,(78)(79)(80)(81). Cancer/ immortalized cell lines can also be used to represent the liver-specific NPCs (82).…”

Section: Establishing In Vitro Liver Models Using Human-based Cellsmentioning

confidence: 99%

“…There is growing evidence indicating that culturing cells in 3D can promote a more in vivo-like phenotype than the same cell type cultured in 2D, when considering hepatocyte function and expression of DMETs (69,71,(87)(88)(89)(90). Consequently, they show greater sensitivity to detect toxicity for known hepatotoxic compounds, when compared to 2D cultures (12,69,81,87). Another major benefit of growing cells in 3D is the ability to culture cells for longer, enabling longer and repeat dosing regimens that more closely resemble those seen in the clinic, which in turn allows the detection of previously undetectable chronic toxicities (e.g., fialuridine) (47,68,71).…”

Section: D Culturesmentioning

confidence: 99%

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Current Perspective: 3D Spheroid Models Utilizing Human-Based Cells for Investigating Metabolism-Dependent Drug-Induced Liver Injury

Cox

Lynch

Goldring

et al. 2020

Front. Med. Technol.

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Drug-induced liver injury (DILI) remains a leading cause for the withdrawal of approved drugs. This has significant financial implications for pharmaceutical companies, places increasing strain on global health services, and causes harm to patients. For these reasons, it is essential that in-vitro liver models are capable of detecting DILI-positive compounds and their underlying mechanisms, prior to their approval and administration to patients or volunteers in clinical trials. Metabolism-dependent DILI is an important mechanism of drug-induced toxicity, which often involves the CYP450 family of enzymes, and is associated with the production of a chemically reactive metabolite and/or inefficient removal and accumulation of potentially toxic compounds. Unfortunately, many of the traditional in-vitro liver models fall short of their in-vivo counterparts, failing to recapitulate the mature hepatocyte phenotype, becoming metabolically incompetent, and lacking the longevity to investigate and detect metabolism-dependent DILI and those associated with chronic and repeat dosing regimens. Nevertheless, evidence is gathering to indicate that growing cells in 3D formats can increase the complexity of these models, promoting a more mature-hepatocyte phenotype and increasing their longevity, in vitro. This review will discuss the use of 3D in vitro models, namely spheroids, organoids, and perfusion-based systems to establish suitable liver models to investigate metabolism-dependent DILI.

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Section: Establishing In Vitro Liver Models Using Human-based Cellsmentioning

confidence: 99%

Section: D Culturesmentioning

confidence: 99%

Current Perspective: 3D Spheroid Models Utilizing Human-Based Cells for Investigating Metabolism-Dependent Drug-Induced Liver Injury

Cox

Lynch

Goldring

et al. 2020

Front. Med. Technol.

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“…Li et al created co-culture spheroids of PHHs and Kupffer cells. Elsewhere, a study comparing PHH spheroids with co-cultured spheroids for evaluation of 14 types of DILI-causing compounds showed that the role of Kupffer cells was compound-dependent [ 50 ]. Hendriks et al evaluated two 3D spheroid models, from PHHs and HepaRG, to detect cholestatic compounds [ 51 ].…”

Section: Recent 3d-culture Studies Using Phhs For Hepatotoxicity Dmentioning

confidence: 99%

“…Cultured human cancer-derived hepatocytes have long been used for human-specific toxicity assessments, but they generally have lower expression levels of drug-metabolizing enzymes than PHHs [ 39 , 40 ]. Various applications of PHH spheroids as pharmacokinetic models [ 41 , 42 , 43 , 44 ] or hepatotoxicity detection models [ 16 , 45 , 46 , 47 , 48 , 49 , 50 , 51 ] have already been reported, and it has become clear that this model is extremely versatile and offers a variety of advantages over 2D cultures ( Table 2 ) [ 16 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 ]. PHH spheroids have also been used as disease models [ 58 , 59 , 60 ].…”

Section: Introductionmentioning

confidence: 99%

Utility of Three-Dimensional Cultures of Primary Human Hepatocytes (Spheroids) as Pharmacokinetic Models

et al. 2020

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This paper reviews the usefulness, current status, and potential of primary human hepatocytes (PHHs) in three-dimensional (3D) cultures, also known as spheroids, in the field of pharmacokinetics (PK). Predicting PK and toxicity means pharmaceutical research can be conducted more efficiently. Various in vitro test systems using human hepatocytes have been proposed as tools to detect hepatic toxicity at an early stage in the drug development process. However, such evaluation requires long-term, low-level exposure to the test compound, and conventional screening systems such as PHHs in planar (2D) culture, in which the cells can only survive for a few days, are unsuitable for this purpose. In contrast, spheroids consisting of PHH are reported to retain the functional characteristics of human liver for at least 35 days. Here, we introduce a fundamental PK and toxicity assessment model of PHH spheroids and describe their applications for assessing species-specific metabolism, enzyme induction, and toxicity, focusing on our own work in these areas. The studies outlined in this paper may provide important information for pharmaceutical companies to reduce termination of development of drug candidates.

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“…Adoption of new techniques in the drug discovery pipeline has been regarded as a solution to this serious issue. Typically, artificial intelligence [1], cell spheroid model [2], organ-on-a-chip [3], organoid [4], 3D bioprinting [5], and similar techniques have been gradually merged into the pharmaceutical industry to increase the efficiency of drug discovery. Among them, the 3D bioprinting technique offers highly biomimetic in vitro models and has attracted considerable attention.…”

Section: Introductionmentioning

confidence: 99%

3D bioprinted breast tumor model for structure–activity relationship study

Deng

Zhuang

et al. 2020

Bio-des. Manuf.

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In this paper, we present a 3D printed tumor spheroidal model suitable for drug discovery. This model is based on a hydroxyethyl cellulose/alginate/gelatin (HCSG) composite biomaterial that has three distinct properties: (1) the HCSG is similar to the commercial basement membrane extract in Ki67, MUC1, and PARP1 expressions of MCF-7 cells for embedding culture; (2) the HCSG is printable at room temperature; and (3) the HCSG can be large-scale manufactured at an ultralow cost.We printed a 3D MCF-7 spheroid model with HCSG and characterized it in terms of cell viability, spheroid size, key protein expression, and mitochondrial metabolic activity. We used the 3D MCF-7 spheroid model to evaluate the anti-breast cancer activity of 13 amino acid-based flavone phosphoramidates and found that the alanine structure induced a stronger drug resistance, whereas phenylalanine hardly caused drug resistance in the MCF-7 cells. This is the first time that 3D bioprinting technology has been used in a structure-activity relationship study.

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Three-Dimensional Spheroids With Primary Human Liver Cells and Differential Roles of Kupffer Cells in Drug-Induced Liver Injury

Cited by 48 publications

References 39 publications

Current Perspective: 3D Spheroid Models Utilizing Human-Based Cells for Investigating Metabolism-Dependent Drug-Induced Liver Injury

Current Perspective: 3D Spheroid Models Utilizing Human-Based Cells for Investigating Metabolism-Dependent Drug-Induced Liver Injury

Utility of Three-Dimensional Cultures of Primary Human Hepatocytes (Spheroids) as Pharmacokinetic Models

3D bioprinted breast tumor model for structure–activity relationship study

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