Induction of three-dimensional assembly of human liver cells by simulated microgravity

Liver failure, notwithstanding advances in medical management, remains a cause of considerable morbidity and mortality in the developed world. Although bioartificial liver (BAL) support systems offer the potential of significant therapeutic benefit for such patients, many issues relating to their use are still to be resolved. In this review, these issues are examined in terms of the functions required, the cells of choice in such a system, and the most appropriate environment to optimize the function of such cells T he development of nonbiological systems to support critically ill patients with acute liver failure (ALF) that incorporate plasmapheresis, 1 charcoal hemoperfusion, 2 and ultrafiltration techniques 3 has not had a significant impact on survival. Consequently, hepatocytebased biological systems have attracted intense interest worldwide but have also generated most of the controversy. Uncertainty exists about the most suitable biological component and the risk for zoonoses and immune rejection in the host. In addition, the optimization of culture conditions and thus metabolic function of the biological component have not been systematically studied, although continuing improvements in these areas have rendered this therapeutic avenue in ALF more promising. To compound matters, the question of which aspects of hepatocyte metabolism in an artificial liver are required to sustain life and promote recovery remains largely unanswered, further limiting development. In this review, the biological substrate of such systems is critically examined and insights are provided into the ideal system.

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“…Again, such modalities are at an experimental stage, and their applicability remains to be confirmed. [67][68][69][70][71][72] …”

Section: Novel Culture Modalitiesmentioning

confidence: 99%

Which hepatocyte will it be? Hepatocyte choice for bioartificial liver support systems

Tsiaoussis

Newsome

Nelson

et al. 2001

Liver Transplantation

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“…The rat pheochromocytoma (PC12) cells cultured in the RWV showed formation of large aggregates exhibiting neuroendocrine differentiation and altered cellular signaling mechanisms (Lelkes et al, 1998). Human hepatocytes formed three-dimensional assemblies when exposed to simulated micro-g (Khaoustov et al, 1999). Cultures of PC12 and SH-SY5Y cells in the simulated micro-g resulted in high cell viability and cell aggregation (Wang and Good, 2001).…”

Section: Introductionmentioning

confidence: 99%

Effect of simulated microgravity on oxidation-sensitive gene expression in PC12 cells

Kwon

Sartor

Tomlinson

et al. 2006

Advances in Space Research

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Oxygen utilization by and oxygen dependence of cellular processes may be different in biological systems that are exposed to microgravity (micro-g). A baseline in which cellular changes in oxygen sensitive molecular processes occur during micro-g conditions would be important to pursue this question. The objective of this research is to analyze oxidation-sensitive gene expression in a model cell line [rat pheochromocytoma (PC12)] under simulated micro-g conditions. The PC12 cell line is well characterized in its response to oxygen, and is widely recognized as a sensitive model for studying the responses of oxygen-sensitive molecular and cellular processes. This study uses the rotating wall vessel bioreactor (RWV) designed at NASA to simulate micro-g. Gene expression in PC12 cells in response to micro-g was analyzed by DNA microarray technology. The microarray analysis of PC12 cells cultured for 4 days under simulated micro-g under standardized oxygen environment conditions revealed more than 100 genes whose expression levels were changed at least twofold (up-regulation of 65 genes and down-regulation of 39 genes) compared with those from cells in the unit gravity (unit-g) control. This study observed that genes involved in the oxidoreductase activity category were most significantly differentially expressed under micro-g conditions. Also, known oxidation-sensitive transcription factors such as hypoxia-inducible factor-2α, c-myc, and the peroxisome proliferator-activated receptor-γ were changed significantly. Our initial results from the gene expression microarray studies may provide a context in which to evaluate the effect of varying oxygen environments on the background of differential gene regulation of biological processes under variable gravity conditions.

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“…can be achieved by culturing primary tissues or established cell lines within extracellular matrix gels, synthetic scaffolds, rotary cell culture systems, or on low/non-adherent culture plastics; [6][7][8][9][10][11] these 3D cell culture techniques all aim to restore the 3D architecture that characterizes normal tissues and solid tumors alike. Studies have shown that gene expression profiles of 3D-cultured cells are dramatically different to monolayer cultures and more closely resemble the profiles of the tissues of origin than their 2D counterparts.…”

mentioning

confidence: 99%

A three-dimensional microenvironment alters protein expression and chemosensitivity of epithelial ovarian cancer cells in vitro

Lee

Mhawech‐Fauceglia

Lee

et al. 2013

Laboratory Investigation

269

125

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For many cancers, there is a real need for more effective therapies. Although many drugs show promising results in vitro, most fail to translate into an in vivo model system, and only B5% show anti-tumor activity in clinical trials. It remains a significant challenge to accurately replicate in vitro the complex in vivo microenvironment in which cancers thrive, but this will be key to increasing the success of translating novel therapies into clinical practice. Three-dimensional (3D) cell culture models may better mimic primary tumors in vivo than traditional two-dimensional (2D) cultures. Therefore, we established and characterized 3D in vitro models of 31 epithelial ovarian cancer (EOC) cell lines, compared their biological and molecular features with 2D cultures and primary tumors, and tested their efficacy as models for evaluating chemoresponse. When cultured in 3D using polyhydroxoethylamethacrylate-coated plastics, EOC lines formed multicellular aggregates that could be classified as 'large dense', 'large loose', and 'small', based on size, light permeability, and proportion of cells incorporated into the complex structures. Features of histological differentiation characteristic of primary tumors that were not present in 2D cultures were restored in 3D. For many cell lines, the transition from a 2D to 3D microenvironment induced changes in the expression of several biomarkers relevant to disease. Generally, EOC cell lines proliferated more slowly and were more chemoresistant in 3D compared with 2D culture. In summary, 3D models of EOCs better reflect the histological, biological, and molecular features of primary tumors than the same cells cultured using traditional 2D techniques; 3D in vitro models also exhibit different sensitivities to chemotherapeutic agents compared with 2D models, which may have a significant impact on the success of drug testing pipelines for EOC. These findings could also impact in vitro modeling approaches and drug development strategies for other solid tumor types. The success rate of anti-cancer therapies translating from in vitro culture systems into the clinic is about 5%. 1 The vast majority of drugs that show promising results in vitro fail to replicate in an in vivo model system and even fewer make it into clinical trials. Nonetheless testing drugs in cell culture models is a vital part of any drug development process. It is likely that a major contributing factor to the low rates of in vivo translation of new therapeutic agents is the widespread use of two-dimensional (2D) monolayer culture systems used for in vitro drug discovery and development. 2D cultures fail to recapitulate the gradients of drugs, nutrients, gases, and waste products that characterize tumors in vivo; all are important factors influencing response to therapy. 2,3 Moreover, many of the signaling pathways involved in chemoresponsiveness are differentially activated in monolayer cultures, and as a result, 2D cultures are often more sensitive to drug therapies yielding many false-positive results in 2D dr...

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Induction of three-dimensional assembly of human liver cells by simulated microgravity

Cited by 109 publications

References 19 publications

Which hepatocyte will it be? Hepatocyte choice for bioartificial liver support systems

Which hepatocyte will it be? Hepatocyte choice for bioartificial liver support systems

Effect of simulated microgravity on oxidation-sensitive gene expression in PC12 cells

A three-dimensional microenvironment alters protein expression and chemosensitivity of epithelial ovarian cancer cells in vitro

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