title: Comparative analysis of human embryonic stem cell and induced pluripotent stem cell-derived hepatocyte-like cells reveals current drawbacks and possible strategies for improved differentiation.
abstract: Hepatocytes derived from human embryonic stem cells (hESCs) or induced pluripotent stem cells (iPSCs) could provide a defined and renewable source of human cells relevant for cell replacement therapies and toxicology studies. However, before patient-specific iPSCs can be routinely used for these purposes, there is a dire need to critically compare these cells to the golden standard--hESCs. In this study, we aimed at investigating the differences and similarities at the transcriptional level between hepatocyte-like cells (HLCs) derived from both hESCs and iPSCs. Two independent protocols for deriving HLCs from hESCs and iPSCs were adopted and further characterization included immunocytochemistry, real-time (RT)-polymerase chain reaction, and in vitro functional assays. Comparative microarray-based gene expression profiling was conducted on these cells and compared to the transcriptomes of human fetal liver and adult liver progenitors. HLCs derived from hESCs and human iPSCs showed significant functional similarities, similar expression of genes important for liver physiology and common pathways. However, specific differences between the 2 cell types could be observed. For example, among the cytochrome P450 gene family, CYP19A1, CYP1A1, and CYP11A1 were enriched in hESC-derived HLCs, and CYP46A1 and CYP26A1 in iPSC-derived HLCs. HLCs derived from hESCs and human iPSCs exhibited broad similarities but as well meaningful differences. We identified common upregulated transcription factors, which might serve as a source for generating a cocktail of factors able to directly transdifferentiate somatic cells into HLCs. The findings may be vital to the refinement of protocols for the efficient derivation of functional patient-specific HLCs for regenerative and toxicology studies.
authors.affiliation: Molecular Embryology and Aging Group, Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Justyna
authors.initials: J
authors.lastname: Jozefczuk
authors.forename: Alessandro
authors.initials: A
authors.lastname: Prigione
authors.forename: Lukas
authors.initials: L
authors.lastname: Chavez
authors.forename: James
authors.initials: J
authors.lastname: Adjaye
mesh_terms: D000704:Analysis of Variance; D002454:Cell Differentiation; D002460:Cell Line; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology*; D020869:Gene Expression Profiling; D006003:Glycogen / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology*; D006801:Humans; D007150:Immunohistochemistry; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D008099:Liver / Q000378:metabolism; D016133:Polymerase Chain Reaction; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D014157:Transcription Factors; D006003:Glycogen; D003577:Cytochrome P-450 Enzyme System