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The iPSC-ESC Gap

Stem cells created from mature cells, called induced pluripotent stem cells, retain a distinct ‘memory’ of their former purpose that might limit their potential for therapeutic use.

Induced pluripotent stem (iPS) cells — adult cells that have been de-differentiated into an embryonic-like state — have “hotspots” in their genomes that are not completely reprogrammed, according to a new study in Nature.

  • The research demonstrates that iPS cells are fundamentally different from embryonic stem (NYSE:ES) cells, and will require more analysis prior to use in therapies and disease models.

After producing the first genome-wide methylation maps of human ES cells and somatic cells in 2009, Joseph Ecker and colleagues at the Salk Institute turned their sights on mapping methylation, the addition of methyl groups to DNA, which can affect gene expression in iPS cells.

  • The team generated whole-genome DNA methylation profiles, at a single-base resolution, for 11 cell lines, including iPS cells derived using a range of technologies, ES cells, differentiated iPS and ES cells, and parent cell lines: fibroblasts, adipose cells, and embryonic lung cells;
  • Notably, the team mapped not just CG methylation, the standard type of methylation analyzed in most studies, but also non-CG methylation, which Ecker previously showed makes up 25% of the methylation in ES cells but is rarely present in somatic cells;
  • The iPS and ES cells shared global patterns of methylation, but as the team zoomed in for a closer look, the differences were striking. They identified 1,175 regions in iPS cells with different methylation patterns than ES cells, including 22 large regions, or “hotspots,” where iPS cells lacked the non-CG methylation characteristic of ES cells;
  • The somatic cells from which the iPS cells were derived also lack these non-CG methylation zones, suggesting that iPS cells fail to acquire these changes as they are de-differentiated into a stem cell-like state;
  • Additionally, the researchers found that iPS cell hotspots were retained after re-differentiation into various cell types, which could have consequences for cells derived from iPS cells.

The Bottom Line: The findings complement 2 studies published last year, 1 by Daley’s lab and another by Konrad Hochedlinger and colleagues at Harvard finding that mouse iPS cells retain an “epigenetic memory” of the cell type from which they were derived, a footprint that can affect the cells’ ability to develop into different lineages.  iPS is a really powerful technology and the hotspots can hopefully be used as diagnostic markers for scientists to evaluate iPS cells.