Genes and stem cell pluripotency
9 February 2009
Embryonic stem (ES) cells have the remarkable ability to both self-renew and create all of the other cell types of the body. A crucial question is how they manage to maintain this pluripotency. Research from Austin Smith at the Wellcome Trust Centre for Stem Cell Research in Cambridge and Ian Chambers in Edinburgh is revealing how a gene called Nanog may play a crucial role.
Nanog is known to be important in the ES cell state, but its exact role has been unclear. Now, Dr Chambers, Professor Smith and colleagues have found that levels of Nanog protein fluctuate in ES cells. Cells with low levels - or lacking Nanog entirely - can still self-renew but are more prone to differentiate. This suggests that Nanog is not absolutely required for self-renewal, but acts as a generic inhibitor of differentiation.
In fact, with colleagues in the USA and Canada, Professor Smith has found that self-renewal may be an innate property of ES cells. It had been thought that external signals were needed to keep ES cells self-renewing, but when all external signals were eliminated, ES cells endlessly self-renewed without differentiating.
The emerging picture suggests that Nanog contributes to ES cells’ intrinsic self-renewal capacity, by blocking differentiation. But fluctuating levels mean that occasionally cells have a ‘window of opportunity’ in which they can escape Nanog control and begin differentiating.
An insight into the possible mechanisms of Nanog action has come from Dr Chambers’s work linking pluripotency to X inactivation - the epigenetic silencing of one X chromosome in female (XX) cells. In ES cells, unlike most other cells, both X chromosomes are active. When they begin to differentiate, X inactivation is re-established.
This timing suggested that Nanog and other pluripotency factors could be involved - and sure enough, when they were absent, reversal of X inactivation was disrupted.
Significantly, as well as tying together the processes of X inactivation and pluripotency, these findings link Nanog to epigenetic regulation of gene activity. Thus Nanog may act at least in part by controlling epigenetic programming of cells.
This research was supported by a range of funders, including the Wellcome Trust.
Image: Embryonic stem cells.
References
Silva J, Smith A. Capturing pluripotency. Cell 2008;132(4):532-6.
Chambers I et al. Nanog safeguards pluripotency and mediates germline development. Nature 2007;450(7173):1230-4.
Ying Q-L et al. The ground state of embryonic stem cell self-renewal. Nature 2008;453(7194):519-23.
Navarro P et al. Molecular coupling of Xist regulation and pluripotency. Science 2008;321(5896):1693-5.