Persistent Donor Cell Gene Expression among Human Induced Pluripotent Stem Cells Contributes to Differences with Human Embryonic Stem Cells

University of Calgary, Canada
PLoS ONE (Impact Factor: 3.23). 02/2010; 5(2):e8975. DOI: 10.1371/journal.pone.0008975
Source: PubMed


Human induced pluripotent stem cells (hiPSCs) generated by de-differentiation of adult somatic cells offer potential solutions for the ethical issues surrounding human embryonic stem cells (hESCs), as well as their immunologic rejection after cellular transplantation. However, although hiPSCs have been described as "embryonic stem cell-like", these cells have a distinct gene expression pattern compared to hESCs, making incomplete reprogramming a potential pitfall. It is unclear to what degree the difference in tissue of origin may contribute to these gene expression differences. To answer these important questions, a careful transcriptional profiling analysis is necessary to investigate the exact reprogramming state of hiPSCs, as well as analysis of the impression, if any, of the tissue of origin on the resulting hiPSCs. In this study, we compare the gene profiles of hiPSCs derived from fetal fibroblasts, neonatal fibroblasts, adipose stem cells, and keratinocytes to their corresponding donor cells and hESCs. Our analysis elucidates the overall degree of reprogramming within each hiPSC line, as well as the "distance" between each hiPSC line and its donor cell. We further identify genes that have a similar mode of regulation in hiPSCs and their corresponding donor cells compared to hESCs, allowing us to specify core sets of donor genes that continue to be expressed in each hiPSC line. We report that residual gene expression of the donor cell type contributes significantly to the differences among hiPSCs and hESCs, and adds to the incompleteness in reprogramming. Specifically, our analysis reveals that fetal fibroblast-derived hiPSCs are closer to hESCs, followed by adipose, neonatal fibroblast, and keratinocyte-derived hiPSCs.

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    • "The claim, in dozens of reports, that epigenetic relics of somatic origin, including DNA methylation and gene expression, remain in iPSCs, distinguishes iPSCs from ESCs despite their shared pluripotency6667686970717273. On the other hand, many other reports have demonstrated that no distinct differences (including differences in epigenetic memory) exist between ESCs and iPSCs[[77]. "
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    • "Several studies have suggested that iPS cells might retain a certain degree of epigenetic memory similar to somatic cells from which they are derived from [34] [35] [36] [37]. This retention of epigenetic memory might involve histone modification [36] and DNA methylation [37]. "
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    • "Recent research has shown than the continuous passage of iPSCs can attenuate transcriptional, epigenetic, and functional differences (Hanna et al., 2010; Sullivan et al., 2010). Another study has identified that donor cell–specific gene expression patterns of human iPSCs in early passages are different from those in latepassage cells (Ghosh et al., 2010), suggesting an influence of continuous passage on the molecular properties of the resultant iPSCs. However, both studies only focused on the expression of differentiated genes and did not examine the effect on the expression of pluripotent genes in iPSCs by continuous passage. "
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