In Vitro Differentiated Adult Human Liver Progenitor Cells Display Mature Hepatic Metabolic Functions: A Potential Tool for in Vitro Pharmacotoxicological Testing

Author:

Khuu Dung Ngoc1,Scheers Isabelle1,Ehnert Sabrina2,Jazouli Nawal1,Nyabi Omar1,Buc-Calderon Pedro3,Meulemans Ann4,Nussler Andreas2,Sokal Etienne1,Najimi Mustapha1

Affiliation:

1. Institut de Recherche Clinique et Expérimentale (IREC), Laboratory of Pediatric Hepatology and Cell Therapy, Université Catholique de Louvain, Brussels, Belgium

2. Department of Traumatology, Technical University Munich, Munich, Germany

3. Louvain Drug Research Institute, Toxicology and Cancer Biology Research Group, PMNT Unit, Université Catholique de Louvain, Brussels, Belgium

4. Laboratoire de Pédiatrie, Unité Métabolique, Université Libre de Bruxelles, Brussels, Belgium

Abstract

The potential use of stem/progenitor cells as alternative cell sources to mature hepatocytes remains basically dependent on their ability to exhibit some, if not all, the metabolic liver functions. In the current study, four major liver functions were investigated in adult derived human liver stem/progenitor cell (ADHLSCs) populations submitted to in vitro hepatogenic differentiation: gluconeogenesis, ammonia detoxification, and activity of phase I and phase II drug-metabolizing enzymes. These acquired hepatic activities were compared to those of primary adult human hepatocytes, the standard reference. Amino acid content was also investigated after hepatogenic differentiation. Differentiated ADHLSCs display higher de novo synthesis of glucose correlated to an increased activity of glucose-6 phosphatase and mRNA expression of key related enzymes. Differentiated ADHLSCs are also able to metabolize ammonium chloride and to produce urea. This was correlated to an increase in the mRNA expression of relevant key enzymes such arginase. With respect to drug metabolism, differentiated ADHLSCs express mRNAs of all the major cytochromes investigated, among which the CYP3A4 isoform (the most important drug-metabolizing enzyme). Such increased expression is correlated to an enhanced phase I activity as independently demonstrated using fluorescence-based assays. Phase II enzyme activity and amino acid levels also show a significant enhancement in differentiated ADHLSCs. The current study, according to data independently obtained in different labs, demonstrates that in vitro differentiated ADHLSCs are able to display advanced liver metabolic functions supporting the possibility to develop them as potential alternatives to primary hepatocytes for in vitro settings.

Publisher

SAGE Publications

Subject

Transplantation,Cell Biology,Biomedical Engineering

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