Involvement of Cell Junctions in Hepatocyte Culture Functionality

Vinken, Mathieu; Papeleu, Peggy; Snykers, Sarah; Rop, Evelien De; Henkens, Tom; Chipman, J.K.; Rogiers, Vera; Vanhaecke, Tamara

doi:10.1080/10408440600599273

Cited by 89 publications

(104 citation statements)

References 273 publications

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“…In particular, the maintenance of physiological cell-cell contacts has been shown to be crucial for the preservation of the mature hepatic phenotype. 115 Under this view, hepatic differentiation was performed in differently scaled 3D culture models. Microscale approaches are mainly based on 3D cell aggregation in matrices like collagen, 116 alginate, 117 hydrogel, 118 or Matrigel.…”

Section: Human Pluripotent Stem Cellsmentioning

confidence: 99%

Cell sources forin vitrohuman liver cell culture models

Zeilinger

Freyer

Damm

et al. 2016

Exp Biol Med (Maywood)

168

144

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In vitro liver cell culture models are gaining increasing importance in pharmacological and toxicological research. The source of cells used is critical for the relevance and the predictive value of such models. Primary human hepatocytes (PHH) are currently considered to be the gold standard for hepatic in vitro culture models, since they directly reflect the specific metabolism and functionality of the human liver; however, the scarcity and difficult logistics of PHH have driven researchers to explore alternative cell sources, including liver cell lines and pluripotent stem cells. Liver cell lines generated from hepatomas or by genetic manipulation are widely used due to their good availability, but they are generally altered in certain metabolic functions. For the past few years, adult and pluripotent stem cells have been attracting increasing attention, due their ability to proliferate and to differentiate into hepatocyte-like cells in vitro. However, controlling the differentiation of these cells is still a challenge. This review gives an overview of the major human cell sources under investigation for in vitro liver cell culture models, including primary human liver cells, liver cell lines, and stem cells. The promises and challenges of different cell types are discussed with a focus on the complex 2D and 3D culture approaches under investigation for improving liver cell functionality in vitro. Finally, the specific application options of individual cell sources in pharmacological research or disease modeling are described.

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Section: Human Pluripotent Stem Cellsmentioning

confidence: 99%

Cell sources forin vitrohuman liver cell culture models

Zeilinger

Freyer

Damm

et al. 2016

Exp Biol Med (Maywood)

168

144

View full text Add to dashboard Cite

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“…It then translocates into the nucleus where it transactivates target genes by binding to transcriptional activators of the T-cell factor/lymphoid-enhancing factor (TCF/Lef) family (MacDonald et al, 2009). In parallel to its transcriptional activity, CTNNB1 participates in adherens junction formation by interacting with E-cadherin and a-catenin, linking cadherins to the actin cytoskeleton (Vinken et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

The WNT/β-Catenin Pathway Is a Transcriptional Regulator of CYP2E1,CYP1A2, and Aryl Hydrocarbon Receptor Gene Expression in Primary Human Hepatocytes

et al. 2014

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The wingless-type MMTV integration site family (WNT)/b-catenin/ adenomatous polyposis coli (CTNNB1/APC) pathway has been identified as a regulator of drug-metabolizing enzymes in the rodent liver. Conversely, little is known about the role of this pathway in drug metabolism regulation in human liver. Primary human hepatocytes (PHHs), which are the most physiologically relevant culture system to study drug metabolism in vitro, were used to investigate this issue. This study assessed the link between cytochrome P450 expression and WNT/b-catenin pathway activity in PHHs by modulating its activity with recombinant mouse Wnt3a (the canonical activator), inhibitors of glycogen synthase kinase 3b, and small-interfering RNA to invalidate CTNNB1 or its repressor APC, used separately or in combination. We found that the WNT/ b-catenin pathway can be activated in PHHs, as assessed by universal b-catenin target gene expression, leucine-rich repeat containing G protein-coupled receptor 5. Moreover, WNT/ b-catenin pathway activation induces the expression of CYP2E1, CYP1A2, and aryl hydrocarbon receptor, but not of CYP3A4, hepatocyte nuclear factor-4a, or pregnane X receptor (PXR) in PHHs. Specifically, we show for the first time that CYP2E1 is transcriptionally regulated by the WNT/b-catenin pathway. Moreover, CYP2E1 induction was accompanied by an increase in its metabolic activity, as indicated by the increased production of 6-OH-chlorzoxazone and by glutathione depletion after incubation with high doses of acetaminophen. In conclusion, the WNT/b-catenin pathway is functional in PHHs, and its induction in PHHs represents a powerful tool to evaluate the hepatotoxicity of drugs that are metabolized by CYP2E1.

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“…Gap junctions are composed of two hemichannels of neighbouring cells, which in turn are built up by six transmembrane connexin (Cx) proteins (Figure 1). More than 20 connexin paralogues have been characterised in human and rodents, all which are expressed in a cell type-specifi c manner and are named according to their molecular weight (Decrock et al, 2009;Vinken et al, 2006aVinken et al, , 2006bVinken et al, , 2009aVinken et al, , 2009bVinken et al, , 2008Vinken et al, , 2011. Gap junctions play key roles as goalkeepers in virtually all aspects of tissue homeostasis, including cell growth, cellular differentiation and cell death.…”

Section: Introductionmentioning

confidence: 99%

Modifications in Connexin Expression in Liver Development and Cancer

Vinken

Kock

Oliveira

et al. 2012

Cell Communication & Adhesion

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The establishment of an elaborate gap junctional intercellular communication network, especially between hepatocytes, is important for normal liver development. In fact, the production of the gap junction building blocks, the connexins, undergoes several well-defi ned changes throughout the hepatic differentiation process. This ultimately results in the acquisition of an adult connexin expression pattern which is critical for maintaining the fully differentiated hepatocyte-specifi c phenotype. Abnormalities of connexin production are observed in a number of pathological conditions, such as during liver cancer. This article provides an overview of these processes with emphasis on the underlying molecular mechanisms.

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Involvement of Cell Junctions in Hepatocyte Culture Functionality

Cited by 89 publications

References 273 publications

Cell sources forin vitrohuman liver cell culture models

Cell sources forin vitrohuman liver cell culture models

The WNT/β-Catenin Pathway Is a Transcriptional Regulator of CYP2E1,CYP1A2, and Aryl Hydrocarbon Receptor Gene Expression in Primary Human Hepatocytes

Modifications in Connexin Expression in Liver Development and Cancer

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