Resemblance of the human liver sinusoid in a fluidic device with biomedical and pharmaceutical applications
Open Access
- 13 July 2018
- journal article
- research article
- Published by Wiley in Biotechnology and Bioengineering
- Vol. 115 (10) , 2585-2594
Abstract
Maintenance of the complex phenotype of primary hepatocytes in vitro represents a limitation for developing liver support systems and reliable tools for biomedical research and drug screening. We herein aimed at developing a biosystem able to preserve human and rodent hepatocytes phenotype in vitro based on the main characteristics of the liver sinusoid: unique cellular architecture, endothelial biodynamic stimulation, and parenchymal zonation. Primary hepatocytes and liver sinusoidal endothelial cells (LSEC) were isolated from control and cirrhotic human or control rat livers and cultured in conventional in vitro platforms or within our liver‐resembling device. Hepatocytes phenotype, function, and response to hepatotoxic drugs were analyzed. Results evidenced that mimicking the in vivo sinusoidal environment within our biosystem, primary human and rat hepatocytes cocultured with functional LSEC maintained morphology and showed high albumin and urea production, enhanced cytochrome P450 family 3 subfamily A member 4 (CYP3A4) activity, and maintained expression of hepatocyte nuclear factor 4 alpha (hnf4α) and transporters, showing delayed hepatocyte dedifferentiation. In addition, differentiated hepatocytes cultured within this liver‐resembling device responded to acute treatment with known hepatotoxic drugs significantly different from those seen in conventional culture platforms. In conclusion, this study describes a new bioengineered device that mimics the human sinusoid in vitro, representing a novel method to study liver diseases and toxicology.Keywords
Funding Information
- Consejo Superior de Investigaciones Científicas (PIE‐201450E116)
- Instituto de Salud Carlos III (iPFIS IFI15/00037, iPFIS IFI16/00016, CD15/00050, FIS PI17/00012)
- European Regional Development Fund
- Generalitat de Catalunya
This publication has 40 references indexed in Scilit:
- Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADMEArchives of Toxicology, 2013
- Hepatic Stellate Cell-Mediated Three-Dimensional Hepatocyte and Endothelial Cell Triculture ModelTissue Engineering Part A, 2011
- Inductive angiocrine signals from sinusoidal endothelium are required for liver regenerationNature, 2010
- Network Analysis of Primary Hepatocyte Dedifferentiation Using a Shotgun Proteomics ApproachJournal of Proteome Research, 2010
- Microenvironmental regulation of the sinusoidal endothelial cell phenotype in vitro #Hepatology, 2009
- Evaluation of HepaRG Cells as an in Vitro Model for Human Drug Metabolism StudiesDrug Metabolism and Disposition, 2008
- Enhanced vasoconstrictor prostanoid production by sinusoidal endothelial cells increases portal perfusion pressure in cirrhotic rat liversJournal of Hepatology, 2007
- COMPARISON OF PRIMARY HUMAN HEPATOCYTES AND HEPATOMA CELL LINE HEPG2 WITH REGARD TO THEIR BIOTRANSFORMATION PROPERTIESDrug Metabolism and Disposition, 2003
- Liver sinusoidal endothelial cells are responsible for nitric oxide modulation of resistance in the hepatic sinusoids.Journal of Clinical Investigation, 1997
- Structure and Function of Sinusoidal Lining Cells in the LiverToxicologic Pathology, 1996