Cell-cell interactions are essential for maintenance of hepatocyte function in collagen gel but not on matrigel

Moghe, Prabhas V.; Coger, Robin N.; Toner, Mehmet; Yarmush, Martin L.

doi:10.1002/(sici)1097-0290(19971220)56:6<706::aid-bit14>3.0.co;2-5

Cited by 67 publications

(37 citation statements)

References 18 publications

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“…16,34,41 Heparan sulfate proteoglycan is a major component of the liver basement membrane, which is synthesized by LSECs but not by hepatocytes or liver fibroblasts. 42 In addition, this proteoglycan is naturally found in Matrigel but not in collagen type I, suggesting that it might be picked up during spheroid formation.…”

Section: Discussionmentioning

confidence: 99%

“…16,17 Analysis of the hepatic synthetic function (albumin, urea) and of hepatic metabolism (cytochrome P450 activity) showed that these three methods can maintain a high level of liverspecific function for over 4 weeks in vitro. However, analysis of LDL uptake in cultured hepatocytes was limited to nonpolarized cell lines such as HepG2, possibly due to loss of LDL-R expression in primary cultured hepatocytes.…”

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confidence: 99%

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Liver endothelial cells promote LDL-R expression and the uptake of HCV-like particles in primary rat and human hepatocytes

et al. 2006

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Low-density lipoprotein (LDL) is an important carrier of plasma cholesterol and triglycerides whose concentration is regulated by the liver parenchymal cells. Abnormal LDL regulation is thought to cause atherosclerosis, while viral binding to LDL has been suggested to facilitate hepatitis C infection. Primary hepatocytes quickly lose the ability to clear LDL during in vitro culture. Here we show that the coculture of hepatocytes with liver sinusoidal endothelial cells (LSEC) significantly increases the ability of hepatocytes to uptake LDL in vitro. LDL uptake does not increase when hepatocytes are cocultured with other cell types such as fibroblasts or umbilical vein endothelial cells. We find that LSECs induce the hepatic expression of the LDL receptor and the epidermal growth factor receptor. In addition, while hepatocytes in single culture did not take up hepatitis C virus (HCV)-like particles, the hepatocytes cocultured with LSECs showed a high level of HCV-like particle uptake. We suggest that coculture with LSECs induces the emergence of a sinusoidal surface in primary hepatocytes conducive to the uptake of HCV-like particles. In conclusion, our findings describe a novel model of polarized hepatocytes in vitro that can be used for the study of LDL metabolism and hepatitis C infection. L ow-density lipoprotein (LDL) is a plasma-carried particle whose lipid component includes cholesterol and triglycerides. 1 LDL originates from very low-density lipoprotein (vLDL) synthesized by the liver with apoprotein B-100. The vLDL is converted to LDL by an endothelial lipase, which releases free fatty acids, increasing the density of the particle to form LDL. Excess LDL is then taken up by hepatocytes through LDL receptor (LDL-R)-mediated endocytosis. 1 Improper hepatic clearance of LDL results in elevated plasma levels of LDL which is a serious risk factor for the development of atherosclerosis. 2 One of the first steps in atherosclerosis is the passage of LDL into the vascular wall. Once trapped in the vessel wall, LDL can undergo oxidation. 3 Oxidized LDL is no longer a ligand for the LDL receptor. 4 Accumulation of oxidized LDL and LDL aggregates in the vessel wall stimulates an inflammatory response causing endothelial injury, macrophage recruitment, foam cell formation, and smooth muscle cell proliferation. 3 Current therapeutic intervention includes administration of statins, which block cholesterol production and increase expression of the LDL-R by the liver parenchymal cells, 2 removing LDL from circulation. 5 In addition, liver sinusoidal endothelial cells (LSECs) remove oxidized LDL from the circulation via the scavenger cell receptor. 5 LDL-and LDL-R-mediated pathways have also been shown to play a role in hepatitis C virus (HCV) infection. 6 The HCV surface receptors, glycoproteins E1 and E2, have been shown to associate with LDL and vLDL. 7 The virus particle itself was shown to associate with the

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Section: Discussionmentioning

confidence: 99%

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Liver endothelial cells promote LDL-R expression and the uptake of HCV-like particles in primary rat and human hepatocytes

et al. 2006

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“…Besides the cell-ECM interaction, the defined pore size of the scaffolds, which is achieved during fabrication, enables the establishment of cell-cell contacts which are essential for the maintenance of hepatic function [55]. Naturally derived scaffolds are either based on a single macromolecular carrier, such as chitin, alginate, chitosan, and gelatin, or on mixtures of these macromolecules [46,49].…”

Section: 2d Cultivation Models For Hepatocytesmentioning

confidence: 99%

3D Cultivation Techniques for Primary Human Hepatocytes

et al. 2015

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One of the main challenges in drug development is the prediction of in vivo toxicity based on in vitro data. The standard cultivation system for primary human hepatocytes is based on monolayer cultures, even if it is known that these conditions result in a loss of hepatocyte morphology and of liver-specific functions, such as drug-metabolizing enzymes and transporters. As it has been demonstrated that hepatocytes embedded between two sheets of collagen maintain their function, various hydrogels and scaffolds for the 3D cultivation of hepatocytes have been developed. To further improve or maintain hepatic functions, 3D cultivation has been combined with perfusion. In this manuscript, we discuss the benefits and drawbacks of different 3D microfluidic devices. For most systems that are currently available, the main issues are the requirement of large cell numbers, the low throughput, and expensive equipment, which render these devices unattractive for research and the drug-developing industry. A higher acceptance of these devices could be achieved by their simplification and their compatibility with high-throughput, as both aspects are of major importance for a user-friendly device.

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“…In addition to cell-ECM interactions, cell-cell contacts appear to play a significant role, and studies have shown that spheroid formation is inhibited if the initial cell plating density is too high or too low (Peshwa et al, 1996(Peshwa et al, , 1994. Cellcell interactions are also important in maintaining the viability and functionality of the hepatocytes (Moghe et al, 1997).…”

Section: Riccalton-banks)mentioning

confidence: 99%

A Mathematical Model of Liver Cell Aggregation In Vitro

et al. 2008

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"Authors may self-archive the author's accepted manuscript of their articles on their own websites. Authors may also deposit this version of the article in any repository, provided it is only made publicly available 12 months after official publication or later. He/ she may not use the publisher's version (the final article), which is posted on SpringerLink and other Springer websites, for the purpose of self-archiving or deposit. Furthermore, the author may only post his/her version provided acknowledgement is given to the original source of publication and a link is inserted to the published article on Springer's website. The link must be accompanied by the following text: "The final publication is available at link.springer.com"". th March, 2014A mathematical model of liver cell aggregation in vitroThe behaviour of mammalian cells within three-dimensional structures is an area of intense biological research and underpins the efforts of tissue engineers to regenerate human tissues for clinical applications. In the particular case of hepatocytes (liver cells), the formation of spheroidal multicellular aggregates has been shown to improve cell viability and functionality compared to traditional monolayer culture techniques.We propose a simple mathematical model for the early stages of this aggregation process, when cell clusters form on the surface of the extracellular matrix (ECM) layer on which they are seeded. We focus on interactions between the cells and the viscoelastic ECM substrate. Governing equations for the cells, culture medium and ECM are derived using the principles of mass and momentum balance. The model is then reduced to a system of four partial differential equations, which are investigated analytically and numerically. The model predicts that, provided cells are seeded at a suitable density, aggregates with clearly defined boundaries and a spatially uniform cell density on the interior will form. While the mechanical properties of the ECM do not appear to have a significant effect, strong cell-ECM interactions can inhibit, or possibly prevent, the formation of aggregates. The paper concludes with a discussion of our key findings and suggestions for future work.

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Cell-cell interactions are essential for maintenance of hepatocyte function in collagen gel but not on matrigel

Cited by 67 publications

References 18 publications

Liver endothelial cells promote LDL-R expression and the uptake of HCV-like particles in primary rat and human hepatocytes

Liver endothelial cells promote LDL-R expression and the uptake of HCV-like particles in primary rat and human hepatocytes

3D Cultivation Techniques for Primary Human Hepatocytes

A Mathematical Model of Liver Cell Aggregation In Vitro

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