Abstract
Human iPS cells have been generated using a diverse range of tissues from a variety of donors using different reprogramming vectors. However, these cell lines are heterogeneous, which presents a limitation for their use in disease modeling and personalized medicine. To explore the basis of this heterogeneity we generated 25 iPS cell lines under normalised conditions from the same set of somatic tissues across a number of donors. RNA-seq data sets from each cell line were compared to identify the majority contributors to transcriptional heterogeneity. We found that genetic differences between individual donors were the major cause of transcriptional variation between lines. In contrast, residual signatures from the somatic cell of origin, so called epigenetic memory, contributed relatively little to transcriptional variation. Thus, underlying genetic background variation is responsible for most heterogeneity between human iPS cell lines. We conclude that epigenetic effects in hIPSCs are minimal, and that hIPSCs are a stable, robust and powerful platform for large-scale studies of the function of genetic differences between individuals. Our data also suggest that future studies using hIPSCs as a model system should focus most effort on collection of large numbers of donors, rather than generating large numbers of lines from the same donor.
Highlights
Induced pluripotent stem cells are the subject of tremendous interest as model systems for studying human disease and development [1,2]
We extracted RNA from the iPS cell lines derived from each of these tissues to give a total of 9 RNA samples from fibroblast-derived Induced pluripotent stem cells (iPSCs) (F-iPSCs), 6 from keratinocyte-derived iPSCs (K-iPSCs) and 10 endothelial progenitor cell (EPC)-derived iPSCs (EiPSCs)
We found that inter-individual transcriptional variation in Human induced pluripotent stem (hiPS) cells (VE,38%) is considerably larger than that between somatic tissue of origin (VE,4%) with an even smaller fraction of transcriptional variation (,1%) explained by differences between iPSCs and ESCs (Fig. 1c)
Summary
Induced pluripotent stem cells (iPSCs) are the subject of tremendous interest as model systems for studying human disease and development [1,2]. Cellular reprogramming to iPSCs is an inefficient process in which stochastic events during clonal selection may fix a variety of alternative epigenetic and transcriptional states[3]. Comparisons between human iPS cells and ES cells are confounded with differences in genetic background because the lines are derived from different donors. Because collection of multiple primary tissues from the same individual is frequently impractical, studies of cellular memory in hiPS cells have often confounded iPS source tissue type and donor genetic background. This is important because many cellular phenotypes, including transcription and methylation, are substantially impacted by genetic differences between individuals [11,12,13]
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