The discovery has implications, not only for a better understanding of stem cells unique characteristics, but also for the process of obtaining them from tissue-specific cells avoiding all the problems associated with embryonic stem cells.
Chromatin - the combination of DNA and protein that when condensed form chromosomes - is organized in two forms: with the genetic material tightly packed, so that genes are hidden, unavailable to be activated in what is called heterochromatin, or as euchromatin, in which case the chromosomal material is open and accessible to the cell machinery involved in gene expression. Different cells have different open/close areas depending of which genes are needed for the cell to perform its function. Stem cells, on the other hand, are known to have their chromosomal material largely open and this has been suggested to be behind their pluripotency but so far nothing has been proved.
Alexandre Gaspar Maia, Miguel Ramalho Santos and colleagues at the University of California, San Francisco and Los Angeles, the Centre for Neuroscience and Cell Biology, at the University of Coimbra, Portugal and the Hebrew University of Jerusalem in Israel have been trying to understand better the molecular mechanisms behind stem cells’ unique characteristics and, just recently, identified several molecules found in much higher quantities in pluripotent cells. From these, one called Chd1 seemed particularly interesting and the work now published investigates a potential link between this gene and embryonic stem cell pluripotency.
For this the researchers used RNA interference (RNAi), a method that allows silencing a specific gene and - by following the changes on the target cell - identifying its function. In fact, gene expression starts by converting the DNA information into a RNA molecule, which then serves as blueprint for the corresponding protein and RNAi acts by binding (so stopping it half way) to the RNA of the gene to be silenced.
In their study Gaspar Maia and colleagues silence Chd1 in mouse embryonic stem (ES) cells to find that not only the cells divide much less but also lose capacity to form primordial tissues while acquiring markers of neural cells so, apparently, losing their undifferentiated state and, consequently, also their pluripotency in the absence of Chd1. Further investigation showed that the Chd1 protein generally binds to euchromatic regions (active regions) in ES cells, and that, when the Chd1 gene is turned off, ES cells have much less euchromatin (so less open, available areas).
Next Miguel Ramalho Santos’ team investigated the role of Chd1 in Induced Pluripotent Stem Cells (or iPS cells). iPS cells are stem cells obtained by re-activating the pluripotency of differentiated tissue cells and are ailed as the alternative to the political problems of ES cells. The fact that they are relatively easy to obtain, being sufficient to over-activated four genes - Oct4, Sox2, Klf4 and cMyc – all involved in switching on and off several others, has also contributed to their overgrowing importance as a future therapeutic tool of choice.
This time the researchers used RNAi to silence Chd1 in already differentiated cells, which then they passed through the iPS induction protocol, to find that the number of reprogrammed ES cells obtained was drastically reduced in comparison to those from normal Chd1 cells showing, that also here Chd1 was crucial for pluripotency.
In conclusion, Gaspar Maia and colleagues show that Chd1 is crucial to maintain stem cells’ pluripotency but also to maintain their chromatin open – so keeping the genes poised to be expressed – suggesting that the two factors are linked. Finally, they also show that Chd1 is crucial for the reprogramming of iPS cells.
This last fact is particularly important because while the use of embryonic stem cells is limited - not only by the ethical disagreements behind their origins but also by the fact that they are not, by norm, related to the patients in which they are to be used -, iPS cells can be “done by measure” and - when free from the technical problems that now limit their use in humans – have an almost unlimited potential. In fact, theoretically iPS could be used to study normal and diseased tissue formation, new medication and disease in general, but also cases of specific patients or to supply these with new healthy cells and tissues without rejection problems. This already has been shown in mice where these cells have been used to treat diseases as diverse as sick cell anaemia (where red blood cells have bizarre shapes and, as result, very short lives) and Parkinson’s disease
But for iPS cells eventually be used in humans it is crucial to understand the mechanisms behind pluripotency and the work of Gaspar Maia and colleagues is an important step in that direction.
Also, one of the fundamental questions when developing protocols to create iPS cells is to assure that they are “real” stem cells so they can become part of the body metabolism without creating disease. By showing that both ES and iPS cells depend on Chd1 to stay pluripotent Gaspar Maia’s work supports the idea that research to produce new stem cells is going on the right direction.
Finally, although all this work has been done in mice, in humans Chd1 is found in much higher quantities on ES cells than on differentiated cells, suggesting that Chd1-associated pluripotency is also used in humans.
Nature– VOL.460 NO.7252 DATED 09 JULY 2009 “Chd1 regulates open chromatin and pluripotency of embryonic stem cells”
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