A twist of fate -- Reprogrammed fibroblasts resemble embryonic stem cells
Stem cell biology takes another exciting leap forward as scientists report that normal tissue cells can be reprogrammed to exhibit many of the properties that are characteristic of embryonic stem cells, including the ability to give rise to multiple cell types and contribute to the germline. These findings, published in the inaugural issue of the journal Cell Stem Cell, published by Cell Press, provide strong support for the rationale that it may be possible to generate stem cells with nearly unlimited potential directly from a patient's own cells, an idea that has significant implications for regenerative therapeutics.
Although transplantation of stem cells generated from human embryos is considered to be a promising option for replacement of damaged or diseased tissues, there are serious difficulties and concerns associated with this methodology. Controversial ethical issues are associated with the use of human embryos, and tissue rejection remains a major concern with stem cell transplants, just as it is for organ transplants. One way to avoid these potential problems is to find a way to reliably reprogram an individual's differentiated tissue cells into cells that behave like embryonic stem cells and can give rise to any fetal or adult cell type.
Recent research discovered that expression of four transcription factors can induce a pluripotent state in adult fibroblasts. Dr. Konrad Hochedlinger from the Massachusetts General Hospital Center for Regenerative Medicine and the Harvard Stem Cell Institute, Dr. Kathrin Plath from the Institute for Stem Cell Biology and Medicine at UCLA, and their colleagues improved this approach and combined it with an efficient selection process, which allowed them to generate induced pluripotent cells from fibroblasts that were, based on the assays used, indistinguishable from ES cells. For example, genome-wide analysis revealed that the induced stem cells were highly similar to embryonic stem cells with regards to global DNA methylation and histone methylation patterns. In addition, female-induced stem cells showed reactivation of the X chromosome that was silenced in differentiated cells and exhibited random X inactivation upon differentiation.
"Our results demonstrate that the ectopic expression of four transcription factors is sufficient to globally reset the epigenetic landscape of fibroblasts into that of pluripotent cells that are remarkably similar to embryonic stem cells," explains Dr. Hochedlinger. Dr. Plath adds "The fact that our induced pluripotent cells are epigenetically similar to ES cells suggests that epigenetic abnormalities will not pose a problem for the potential therapeutic applications of induced pluripotent cells." The researchers went on to show that the induced pluripotent cells could differentiate into numerous cell types, including blood cells in culture and oocytes in animals. Importantly, two related papers being published in the journal Nature demonstrate that similar induced pluripotent cells can also give rise to fertilized embryos and viable offspring, respectively. Future studies are needed to examine whether direct reprogramming of human cells follows these promising patterns observed in mice.
These studies and other recent advances in strategies aimed at generating patient-specific stem cell lines are discussed in the review article by Dr. Shinya Yamanaka in the current issue of Cell Stem Cell.
Cell Press. June 2007.
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