July 26, 2011 | Posted By David Lemberg, M.S., D.C.

Embryonic Stem Cells and iPS Cells — Key Epigenetic Differences

The various flavors of stem cell research continue to be in the news and continue to be featured in peer-reviewed literature and leading scientific publications. Recent reports describe the immunogenic rejection of transplanted induced pluripotent stem cells (iPSCs) even when they have been immunologically matched with the intended recipient1,2

Research involving iPSCs has made remarkably rapid advances since their introduction in 2006.3 But research using embryonic stem cells (ESCs) remains of critical importantance. Reprogramming adult cells using a cocktail of transcription factors restores a primitive pluripotent state. However, reprogrammed cells are significantly different from the pluripotent cells of the embryo’s inner cell mass. Many of these differences have yet to be determined. It would be a grave mistake at present to believe that reprogrammed cells can substitute for pluripotent cells derived from embryos. Both lines of work need to go forward.

One main difference between ESCs and iPSCs is related to the epigenetic status of the respective cells. Previously it was believed that the four-letter genetic code (A–adenine, T–thymine, G–guanine, and C–cytosine) was responsible for a cell’s functional state as well as the specific characteristics of the organism. But this has proved to be far too simplistic. One persistent question focused on how an organism’s cells can be functionally distinct if they all have an identical genetic code. Another persistent question addressed whether environmental factors can impact the expression of the genetic code. In other words, does genetics alone determine an organism’s characteristics or are environment factors involved as well?

Epigenetics addresses both of these questions directly. Epigenetics describes (1) the characteristics of histone proteins bound to sections of DNA strands and (2) various biochemical “marks” attached to specific locations on the DNA chain. Epigenetic phenomena include any gene-regulating activity that does not make changes to the genetic code and is able to persist through one or more cellular generations.

Thus, the genetic code must be regulated in order to lead to the development of coherent, organized, functioning cells, tissues, and organisms. A cell’s DNA accumulates various epigenetic markers over the lifetime of the cell. Sperm and egg cells both contain various histone markers and other types of epigenetic imprinting. Upon fertilization of an egg by a sperm, factors in the egg cytoplasm completely reprogram the sperm DNA. Epigenetic marks and histone modifiers of the sperm DNA are fully removed before DNA replication of the zygote commences. So a key distinction between ESCs and iPSCs is that the stem cells obtained from adult human cells have not undergone removal of their epigenetic marks. The effects of this epigenetic persistence on the usefulness of such induced pluripotent stem cells are undetermined. Much further work needs to be done before these cells may be used for treatment or transplantation.

1Apostolou E, Hochedlinger K: iPS cells under attack. Nature 7350:165-166, 2011

2Zhao T, et al: Immunogenicity of induced pluripotent stem cells. Nature 7350:212-215, 2011

3Takahashi K, Yamanaka S: Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126(4):663-676, 2006

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