Abstract
The aim of the study is to generate a spherical three-dimensional (3D) aggregate of hepatocyte-like cells (HLCs) differentiated from human embryonic stem cells and to investigate the effect of the 3D environment on hepatic maturation and drug metabolism. Quantitative real-time PCR analysis indicated that gene expression of mature hepatocyte markers, drug-metabolizing enzymes, and hepatic transporters was significantly higher in HLCs cultured in the 3D system than in those cultured in a two-dimensional system (p < 0.001). Moreover, hepatocyte-specific functions, including albumin secretion and bile canaliculi formation, were increased in HLCs cultured in the 3D system. In particular, 3D spheroidal culture increased expression of CES1 and BCHE, which encode hepatic esterases (p < 0.001). The enhanced activities of these hepatic esterases were confirmed by the cholinesterase activity assay and the increased susceptibility of HLCs to oseltamivir, which is metabolized by CES1. 3D spheroidal culture enhances the maturation and drug metabolism of stem cell-derived HLCs, and this may help to optimize hepatic differentiation protocols for hepatotoxicity testing.
References
Oct 17, 1998·Toxicology and Applied Pharmacology·H ZaherF J Gonzalez
Mar 10, 2001·Life Sciences·B LaupèzeO Fardel
Jan 23, 2003·The Journal of Pharmacology and Experimental Therapeutics·Maciej J Zamek-GliszczynskiKim L R Brouwer
Mar 12, 2004·Toxicological Sciences : an Official Journal of the Society of Toxicology·Julio C DavilaJames Trosko
Aug 12, 2004·Drug Metabolism and Disposition : the Biological Fate of Chemicals·J Andrew WilliamsSimon E Ball
Aug 8, 2006·The International Journal of Developmental Biology·Hossein BaharvandAli Farrokhi
Sep 13, 2006·The Journal of Pharmacology and Experimental Therapeutics·Deshi ShiBingfang Yan
Apr 28, 2007·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Jun CaiHongkui Deng
Aug 9, 2007·Nature Reviews. Molecular Cell Biology·Francesco PampaloniErnst H K Stelzer
Oct 16, 2007·Journal of Toxicology and Environmental Health. Part a·Lauren M AleksunesJosé E Manautou
Jun 3, 2008·Genes to Cells : Devoted to Molecular & Cellular Mechanisms·Nobuaki ShirakiShoen Kume
Dec 4, 2008·Drug Discovery Today·Bradley A JusticeRobin A Felder
Mar 3, 2010·The Pharmacogenomics Journal·S YamadaA Brooks-Wilson
Jul 1, 2010·Cell Transplantation·Jeoung Eun LeeDong Ryul Lee
Sep 9, 2010·Biotechnology and Bioengineering·Jeanette BierwolfJoerg M Pollok
Oct 12, 2010·Journal of Hepatology·Pau Sancho-BruCatherine Verfaillie
Nov 10, 2011·Molecular Therapy : the Journal of the American Society of Gene Therapy·Kazuo TakayamaHiroyuki Mizuguchi
Nov 22, 2011·Drug Discovery Today·Lilian A Hook
Mar 27, 2012·Biomaterials·Yasuhito NagamotoHiroyuki Mizuguchi
Jul 21, 2012·Drug Metabolism and Pharmacokinetics·Tatsuki Fukami, Tsuyoshi Yokoi
Dec 12, 2012·Biomaterials·Kazuo TakayamaHiroyuki Mizuguchi
Feb 2, 2013·Drug Metabolism Reviews·Eva RamboerMathieu Vinken
Feb 7, 2013·Pharmacotherapy·S Casey LaizureRobert B Parker
Jun 4, 2013·Archives of Toxicology·L SchyschkaA K Nussler
Jul 19, 2013·Development·Shinichiro OgawaGordon Keller
Aug 27, 2013·Archives of Toxicology·Patricio GodoyJan G Hengstler
Jan 28, 2014·PloS One·Richard L GieseckLudovic Vallier
Jul 16, 2015·PloS One·Han-Jin ParkHyemin Kim
May 5, 2016·Scientific Reports·Catherine C BellMagnus Ingelman-Sundberg
Citations
Aug 12, 2018·Genome Biology·Petko Fiziev, Jason Ernst
Oct 12, 2019·Cell Death & Disease·Zhongwen LiJie Hao
Aug 17, 2020·Cytotechnology·Da Yeong RyuWon Hur
Apr 25, 2020·Haematologica·Mania AckermannNico Lachmann