The iPSC-ESC gap
Human cells reprogrammed into multipotent stem cells display fundamental differences from true embryonic stem cells
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 linkurl:Nature.
| Human embryonic stem cells |
Nissim Benvenisty, linkurl:Wikimedia Commons;http://commons.wikimedia.org/wiki/File:Human_embryonic_stem_cells.png
The research demonstrates that iPS cells are fundamentally different from embryonic stem (ES) cells, and will require more analysis prior to use in therapies and disease models.
"The results indicate once again that we still have so much to learn about this fascinating process of reprogramming," said linkurl:George Daley;http://daley.med.harvard.edu/ of Harvard Medical School and Children's Hospital Boston, who was not involved in the research, in an email to The Scientist.
"While iPS cells are remarkably similar to ES cells, this study points out important differences, and gives us an ever more refined view of the nature of iPS cells."
After producing the first genome-wide methylation maps of human ES cells and somatic cells in 2009, linkurl:Joseph Ecker;http://www.salk.edu/faculty/ecker.html 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 percent 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 authors noted.
The findings complement linkurl:two studies published last year;http://www.the-scientist.com/blog/display/57562/ -- one by Daley's lab and another by linkurl:Konrad Hochedlinger;http://www.the-scientist.com/careers/article/display/55793/ and colleagues at Harvard -- that found 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.
The results in no way decrease the importance of iPS technology, emphasized Ecker. "iPS is a really powerful technology," he said, and the hotspots can hopefully be used as diagnostic markers for scientists to evaluate iPS cells. "We need to know whether those cells are being reprogrammed properly, and this provides an assay," he said.
Ecker, J.R. et al., "Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells," Nature, doi:10.1038/nature09798.
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[19th July 2010] *linkurl:Pluripotency not required;http://www.the-scientist.com/blog/display/57120/
[27th January 2010] *linkurl:How to ID human pluripotency;http://www.the-scientist.com/news/display/56050/
[11th October 2009]