Significant Epigenetic Differences Demonstrated Between Embryonic and Induced Pluripotent Stem Cells. (February 3, 2011)

The ethical constraints surrounding the study of embryonic stem cells (ES) have been the principal driving force behind the development and study of induced pluripotent stem cells (iPS).

The question has been posed as to how closely iPS cells resemble ES cells. In a study now published by Lister, et al. Nature doi:10.1038/nature09798 (2011) they demonstrate that there are differences in the patterns of epigenetic changes, i.e. alterations that affect gene expression without changing the DNA sequence, between the two types. As  Chad Cowan, a stem-cell biologist at Massachusetts General Hospital in Boston put it when talking to NatureNews' Elie Dolgin: "They are slightly different creatures."

The study reported in Nature analysed differences in DNA methylation patterns (one type of epigenetic alternation) in the genomes of 15 cell lines. Four human ES cell lines, five iPS cell lines, the tissues from which they were derived, and several differentiated cells developed from both kinds of stem cells. "If you look with blinders on, they look fairly similar," says Joseph Ecker, team leader and the paper's corresponding author. "But if you zoom in you find different signatures of what an iPS cell is."

For example the methylation patterns near the tips and centres of chromosomes in the iPS cells resembled those in the adult tissues from which the iPS cells had been derived:  "The reprogramming process, although fascinating, is a fundamentally different way of getting to pluripotency than deriving cells from [embryos]," says George Daley, a stem-cell expert at Children's Hospital Boston in Massachusetts. "We're still looking for reprogramming methods that return cells to the ES-cell-like state."

The work corroborates previous work by Dr Daley and others done in mice. However, in mice the methylation differences could be reset, by extending iPS cell culturing in vitro or through the differentiation to more specialised cell types.

But in human iPS cells, the epigenetic marks remain even after the iPS cells had been redifferentiated to form specific tissues.

Not that ES cells don't have some questions regarding their suitability as model undifferentiated cell types. As NatureNews reports: "In separate work published last month, a team led by Jeanne Loring, a stem-cell researcher at the Scripps Research Institute in La Jolla, found that ES cells tended to contain duplicated chunks of DNA linked to genes associated with self-renewal while iPS cells incorporated extra cancer-causing genes and fewer tumour-suppressor genes."

 According to Richard Young, a stem-cell biologist at the Whitehead Institute in Cambridge, Massachusetts: "When we culture cells outside a normal organism they can acquire features that may not be compatible with life once they go back into an organism."

Finally, William Lowry, a stem-cell biologist at the University of California, Los Angeles sums up matters: "The problem is that we don't know if any of these differences are going to be consequential."