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One Standardized Differentiation Procedure Robustly Generates Homogenous Hepatocyte Cultures Displaying Metabolic Diversity from a Large Panel of Human Pluripotent Stem Cells

Journal article
Authors A. Asplund
A. Pradip
M. Van Giezen
A. Aspegren
H. Choukair
M. Rehnstrom
Nidal Ghosheh
D. El Hajjam
Sandra Holmgren
S. Larsson
J. Benecke
M. Butron
A. Wigander
Karin Noaksson
P. Sartipy
P. Bjorquist
J. Edsbagge
B. Kuppers-Munther
Published in Stem Cell Reviews and Reports
Volume 12
Issue 1
Pages 90-104
ISSN 1550-8943
Publication year 2016
Published at Institute of Biomedicine
Pages 90-104
Language en
Links dx.doi.org/10.1007/s12015-015-9621-...
Keywords Hepatocyte differentiation, Human induced pluripotent stem cells, Human embyronic stem cells, efficient differentiation, epigenetic memory, liver development, hepatic, endoderm, lines, expression, induction, enzyme, donor, hepatotoxicity, Cell Biology, Research & Experimental Medicine, ates of america, v111, p16772, ates of america, v109, p12538
Subject categories Clinical Medicine

Abstract

Human hepatocytes display substantial functional inter-individual variation regarding drug metabolizing functions. In order to investigate if this diversity is mirrored in hepatocytes derived from different human pluripotent stem cell (hPSC) lines, we evaluated 25 hPSC lines originating from 24 different donors for hepatic differentiation and functionality. Homogenous hepatocyte cultures could be derived from all hPSC lines using one standardized differentiation procedure. To the best of our knowledge this is the first report of a standardized hepatic differentiation procedure that is generally applicable across a large panel of hPSC lines without any adaptations to individual lines. Importantly, with regard to functional aspects, such as Cytochrome P450 activities, we observed that hepatocytes derived from different hPSC lines displayed inter-individual variation characteristic for primary hepatocytes obtained from different donors, while these activities were highly reproducible between repeated experiments using the same line. Taken together, these data demonstrate the emerging possibility to compile panels of hPSC-derived hepatocytes of particular phenotypes/genotypes relevant for drug metabolism and toxicity studies. Moreover, these findings are of significance for applications within the regenerative medicine field, since our stringent differentiation procedure allows the derivation of homogenous hepatocyte cultures from multiple donors which is a prerequisite for the realization of future personalized stem cell based therapies.

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