article · Journal of Liver Cancer
Human liver cell models are essential for drug screening, yet standard Huh7 cell lines often lack mature hepatocyte metabolic activity. To address this limitation, three-dimensional hepatic microtissues were constructed using AggreWell technology, combining Huh7 cells, human umbilical vein endothelial cells, Wharton's jelly mesenchymal stem cells, and decellularised liver extracellular matrix microparticles. Huh7 cells were modified with a SINEUP long noncoding RNA to elevate hepatocyte nuclear factor 4 alpha expression. This intervention strengthened hepatocyte-like characteristics, increasing albumin and fibrinogen secretion, urea synthesis, glycogen storage, and cytochrome P450-related gene expression. Concurrently, it suppressed glycolytic genes, lactate production, alpha-fetoprotein secretion, and cell migration. These changes partially restored critical metabolic and functional properties within the engineered microtissues.
Drug discovery relies on accurate laboratory liver models, but conventional human cell lines frequently lose critical metabolic functions. By restoring mature hepatic traits and drug-processing gene expression in engineered microtissues, this method provides a more functional system for screening new medicines. This reduces dependence on scarce primary human liver cells and improves the physiological relevance of safety testing.
This technology is relevant to in vitro drug discovery and toxicity screening, with primary potential users being pharmaceutical developers and contract research organisations. By improving the metabolic reliability of an easily cultured cell line, it could enable more cost-effective, scalable screening assays. The research is currently an applied, early-stage laboratory prototype that requires further industrial validation before integration into commercial testing workflows.
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Background/Aims: Human liver cell-based drug-screening platforms require stable hepatocyte identity and metabolic competence, but Huh7 cells show reduced hepatic function. We investigated whether SINEUP-mediated enhancement of hepatocyte nuclear factor 4 alpha (HNF4α) could improve the metabolic performance of Huh7-based three-dimensional hepatic microtissues. Methods: Decellularized liver extracellular matrix-derived microparticles were incorporated into three-dimensional microtissues containing Huh7 cells, human umbilical vein endothelial cells, and Wharton's jelly mesenchymal stem cells using AggreWell technology. Experimental microtissues were generated with Huh7 cells expressing a SINEUP-based long noncoding RNA targeting HNF4α and were compared with control microtissues. Results: Enhanced HNF4α expression upregulated hepatic markers including HNF4α and albumin, decreased alpha-fetoprotein and CDH2, increased CDH1 expression, suppressed glycolytic genes, modulated lipid metabolism, and increased cytochrome P450-related gene expression. Albumin and fibrinogen secretion, urea synthesis, and glycogen storage increased, whereas alpha-fetoprotein secretion, lactate production, and cell migration decreased. Conclusions: SINEUP-mediated enhancement of HNF4α partially restored hepatocyte-like metabolic and functional properties in Huh7-based hepatic microtissues, supporting their potential use as an in vitro platform for drug discovery and toxicity screening.
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DOI: 10.17998/jlc.2026.05.13
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