Induced Pluripotent Stem Cells and Embryonic Stem Cells Are Distinguished by Gene Expression Signatures

Abstract

SUMMARY Induced pluripotent stem cells (iPSCs) outwardly appear to be indistinguishable from embryonic stem cells (ESCs). A study of gene expression profiles of mouse and human ESCs and iPSCs suggests that, while iPSCs are quite similar to their embryonic counterparts, a recurrent gene expression signature appears in iPSCs regardless of their origin or the method by which they were generated. Upon extended culture, hiPSCs adopt a gene expression profile more similar to hESCs; however, they still retain a gene expression signature unique from hESCs that extends to miRNA expression. Genome-wide data suggested that the iPSC signature gene expression differences are due to differential promoter binding by the reprogramming factors. High-resolution array profiling demonstrated that there is no common specific subkaryotypic alteration that is required for reprogramming and that reprogramming does not lead to genomic instability. Together, these data suggest that iPSCs should be considered a unique subtype of pluripotent cell.

Concise Review: Induced Pluripotent Stem Cells Versus Embryonic Stem Cells: Close Enough or Yet Too Far Apart?

“…One analysis on the whole genome scale found 71 differentially methylated regions (DMR) between three iPSC lines and three ESC lines (and 2,179 between fibroblasts and iPSC) [57]. Almost half of the DMRs show incomplete epigenetic reprogramming of the differentiated cell-of-origin genome, which is in agreement with the gene expression data [24] and epigenetic memory [58]. However, not all the DMR belong to the cell-of-origin memory, indicating that iPSC also accumulate novel aberrant epigenetic states [57,59].…”

“…Chin et al [24] showed that a small group of genes is continuously differentially expressed between several iPSC and ESC lines. Even though those genes couldn't be categorized by gene ontology analysis to the same functional group, they could point to iPSC as being a distinct subtype of pluripotent cells.…”

“…However, when one looks at the individual reprogramming experiments instead of focusing on all differentially expressed genes between multiple iPSC lines and ESC, a statistically significant difference and logic can be seen. Namely, the common features of the deviant transcription come from (a) iPSC not efficiently silencing the expression pattern of the somatic cell from which they are derived and (b) failing to induce some ESC specific genes to the level of expression in ESC, akin to epigenetic memory [24,27,28] (Fig. 2).…”

“…Regarding histone methylation, there are few reports unable to find significant genome-wide differences between iPSC and ESC lines [14,24,61]. Using CHIP-on-CHIP, Chin et al analyzed H3K27me3 and H3K4me3 around the promoters (-5.5 to þ2.5 kb from transcription start site) of 17,000 genes.…”

Two-Phase Analysis of Molecular Pathways Underlying Induced Pluripotent Stem Cell Induction

“…Pioneering work by Yamanaka and colleagues (2006) identified the first set of these dominant factors: Oct4, Sox2, Klf4, and c-Myc (OSKM). Induced pluripotent stem cells (iPSCs) obtained by transduction of these Yamanaka factors or other combinations are epigenetically and developmentally very similar, if not identical, to ESCs [8][9][10][11][12]. Although the identification of factors able to induce this reprogramming represents a major advancement, much work remains to elucidate the exact molecular mechanism underlying this direct cell reprogramming [13].…”