Differentiation of primal stem cells into specialised cells during development is dictated by epigenetic rather than genetic events and is therefore, in principle, reversible. Epigenetic changes include DNA methylation at cytosine residues as well as modifications to the histone proteins that form the scaffold around which the DNA is wound, resulting in heritable changes in DNA accessibility and gene activity.
The teams of researchers at Kyoto University in Japan and the University of Wisconsin, Madison in the United States both used a technique known as nuclear reprogramming to remove this epigenetic code and return the cells to an undifferentiated state. Remarkably, the addition of just four transcription factor genes into the nucleus of adult skin cells is sufficient to reverse the differentiation process and cause the cells to revert back to stem cells. After successfully demonstrating that the cells looked and behaved very much like human embryonic stem cells, the researchers went on to differentiate the cells into cardiac cells, which began spontaneously beating after 12 days, as well as neural and gut epithelial cells.
Although these results come tantalisingly close to the realisation of regenerative medicine, the technique currently relies on a retrovirus to insert the transcription factor genes which presents a potential hazard to human health. Therefore further work is needed to find alternative methods of nuclear reprogramming prior to use of these so-called “induced” pluripotent stem cells in humans.
Comment: Direct reprogramming of terminally differentiated cells from adult humans into undifferentiated stem cells with the capacity to differentiate into any cell in the body is considered by many to be the “holy grail” of stem cell research. This work represents a huge leap forwards for the development of therapeutics derived from human stem cells particularly because skin cells could be taken from individual patients, therefore side-stepping problems associated with immune-based tissue rejection. If the work can be successfully reproduced and developed, it ultimately promises an end to the use of stem cells derived from human embryos and, with it, much of the political controversy and ethical debate surrounding this area of research.