Roles of Spheroid Formation of Hepatocytes in Liver Tissue Engineering

Jiang, Hu‐Lin; Kim, You-Kyoung; Cho, Ki-Hyun; Jang, Young Chul; Choi, Yun‐Jaie; Chung, Joonho; Cho, Chong‐Su

doi:10.15283/ijsc.2010.3.2.69

Cited by 20 publications

(11 citation statements)

References 42 publications

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“…This approach has been developed in the research of cancer (7,76,102), stem cells (17,120), and many organs (such as liver, kidney, heart, etc.) (3,16,64,75). The difficulty in growing physiologically similar 3D tissue or organ cultures stems from finding viable cell types, biocompatible scaffold materials, and a scaffold design that supports the development of an ECM and vascularization.…”

Section: Conclusion and Discussionmentioning

confidence: 99%

Modeling Physiological Events in 2D vs. 3D Cell Culture

et al. 2017

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Cell culture has become an indispensable tool to help uncover fundamental biophysical and biomolecular mechanisms by which cells assemble into tissues and organs, how these tissues function, and how that function becomes disrupted in disease. Cell culture is now widely used in biomedical research, tissue engineering, regenerative medicine, and industrial practices. Although flat, two-dimensional (2D) cell culture has predominated, recent research has shifted toward culture using three-dimensional (3D) structures, and more realistic biochemical and biomechanical microenvironments. Nevertheless, in 3D cell culture, many challenges remain, including the tissue-tissue interface, the mechanical microenvironment, and the spatiotemporal distributions of oxygen, nutrients, and metabolic wastes. Here, we review 2D and 3D cell culture methods, discuss advantages and limitations of these techniques in modeling physiologically and pathologically relevant processes, and suggest directions for future research.

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Section: Conclusion and Discussionmentioning

confidence: 99%

Modeling Physiological Events in 2D vs. 3D Cell Culture

et al. 2017

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“…Accordingly, there have been several reports about the development of in-vitro culture systems for high-functioning hepatocytes37. Spheroid culture of hepatocytes, formed through the rearrangement and compaction of cell aggregates of liver-derived cells including primary hepatocytes or cell lines, yields much higher levels of liver-specific functions than those seen in monolayer culture due to the multiple strong similarities between conditions in spheroid cultures and real tissues, although limitations with respect to the diffusion of oxygen and nutrients into the centers of large spheroids of hepatocytes should be considered38. We also recently reported that primary human hepatocytes as well as HepG2 cells can express higher cell functions when grown in hepatocyte spheroid culture3940.…”

Section: Discussionmentioning

confidence: 99%

Zebularine upregulates expression of CYP genes through inhibition of DNMT1 and PKR in HepG2 cells

Nakamura

Aizawa

Aung

et al. 2017

Sci Rep

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Drug-induced hepatotoxicity is one of the major reasons cited for drug withdrawal. Therefore, it is of extreme importance to detect human hepatotoxic candidates as early as possible during the drug development process. In this study, we aimed to enhance hepatocyte functions such as CYP gene expression in HepG2 cells, one of the most extensively used cell lines in evaluating hepatotoxicity of chemicals and drugs. We found that zebularine, a potent inhibitor of DNA methylation, remarkably upregulates the expression of CYP genes in HepG2 cells. In addition, we revealed that the upregulation of CYP gene expression by zebularine was mediated through the inhibition of both DNA methyltransferase 1 (DNMT1) and double-stranded RNA-dependent protein kinase (PKR). Furthermore, HepG2 cells treated with zebularine were more sensitive than control cells to drug toxicity. Taken together, our results show that zebularine may make HepG2 cells high-functioning and thus could be useful for evaluating the hepatotoxicity of chemicals and drugs speedily and accurately in in-vitro systems. The finding that zebularine upregulates CYP gene expression through DNMT1 and PKR modulation sheds light on the mechanisms controlling hepatocyte function and thus may aid in the development of new in-vitro systems using high-functioning hepatocytes.The liver is essential for maintaining normal physiology and homeostasis of the body. Among its multiple critical roles, the metabolism of chemicals, toxins and drugs by hepatocytes is especially important. Abnormality in homeostasis is often associated with hepatotoxicity 1 . Therefore, a simple and rapid method of assaying a substance's potential for liver damage is needed to predict the toxicity and adverse effects of chemicals for pathophysiological and toxicological purposes 2 . Many preliminary hepatotoxicity studies have been carried out using in-vivo and/or in-vitro animal models, but we should not rely too heavily on such models because of species differences, animal protection concerns and model accuracy issues. Thus more reliable and more practical human in-vitro cell culture models are needed to improve the effectiveness with which we can evaluate the human hepatotoxicity of substances as well as reduce the number of animals used during each drug's development process. In-vitro models using human cells derived from the liver, such as primary hepatocytes and hepatoma cell lines, are preferred 3 . Various sources of hepatic tissue, including whole or partial livers from organ donors or cadavers and resected liver tissue from therapeutic hepatectomies or small surgical biopsies, have been used to generate human hepatocyte cultures4 . Yet hepatocytes originating from these sources sometimes exhibit lower cell viability in culture because they come from diseased livers (e.g., cirrhotic livers) or are damaged during the handling process. Furthermore, it is difficult to guarantee a ready supply of freshly isolated human hepatocytes, and primary human hepatocytes are known to rapidly lose cellular fu...

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“…Reports regarding the biofunctional use of natural polymers in TE scaffolds are currently available . Collagen and HS are the natural components of the liver ECM which immobilize the cells on the substrate via cell adhesion domains onto their molecular chains . The specific amino acid sequence of the collagen protein plays a crucial part in the cell‐scaffold interactions .…”

Section: Introductionmentioning

confidence: 99%

“…7,14 Collagen and HS are the natural components of the liver ECM which immobilize the cells on the substrate via cell adhesion domains onto their molecular chains. [15][16][17] The specific amino acid sequence of the collagen protein plays a crucial part in the cell-scaffold interactions. 17,18 Heparan sulfate (HS) proteoglycans associated with the core protein and sulfate groups are thus formed.…”

Section: Introductionmentioning

confidence: 99%

Improved human endometrial stem cells differentiation into functional hepatocyte‐like cells on a glycosaminoglycan/collagen‐grafted polyethersulfone nanofibrous scaffold

Khademi

Soleimani

et al. 2016

J Biomed Mater Res

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Liver tissue engineering (TE) is rapidly emerging as an effective technique which combines engineering and biological processes to compensate for the shortage of damaged or destroyed liver tissues. We examined the viability, differentiation, and integration of hepatocyte-like cells on an electrospun polyethersulfone (PES) scaffold, derived from human endometrial stem cells (hEnSCs). Natural polymers were separately grafted on plasma-treated PES nanofibers, that is, collagen, heparan sulfate (HS) and collagen-HS. Galactosilated PES (PES-Gal) nanofibrous were created. The engineering and cell growth parameters were considered and compared with each sample. The cellular studies revealed increased cell survival, attachment, and normal morphology on the bioactive natural polymer-grafted scaffolds after 30 days of hepatic differentiation. The chemical and molecular assays displayed hepatocyte differentiation. These cells were also functional, showing glycogen storage, α-fetoprotein, and albumin secretion. The HS nanoparticle-grafted PES nanofibers demonstrated a high rate of cell proliferation, differentiation, and integration. Based on the observations mentioned above, engineered tissue is a good option in the future, for the commercial production of three-dimensional liver tissues for clinical purposes. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 2516-2529, 2017.

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Roles of Spheroid Formation of Hepatocytes in Liver Tissue Engineering

Cited by 20 publications

References 42 publications

Modeling Physiological Events in 2D vs. 3D Cell Culture

Modeling Physiological Events in 2D vs. 3D Cell Culture

Zebularine upregulates expression of CYP genes through inhibition of DNMT1 and PKR in HepG2 cells

Improved human endometrial stem cells differentiation into functional hepatocyte‐like cells on a glycosaminoglycan/collagen‐grafted polyethersulfone nanofibrous scaffold

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