EU-funded scientists in Japan and the UK have shed new light on how stems cells develop into other types of cells. Their discovery that a protein called Nanog lies at the heart of a mechanism that gives stem cells their remarkable properties has important implications for the future use of stem cells in medical applications. The results are published in the journal Cell.

The study was part of the EuroSyStem (European consortium for systematic stem cell biology) project, which was financed with EUR 12 million through the 'Health' Theme of the Seventh Framework Programme (FP7). EuroSyStem's 25 research partner groups study fundamental stem cell biology, combining their expertise in several areas of biology and computational science to generate new knowledge in this important field.

Stem cells are incredibly flexible in that they can develop into any type of cell (e.g. liver, skin or nerve) in a growing organism. This capacity is referred to as pluripotency (literally 'having several potential outcomes') and is the subject of intense investigation. Creating pluripotent cells outside the embryo by reprogramming other cells is possible in the laboratory using a number of methods. However, while scientists are learning more about the process, exactly how these cells are generated is not well understood.

A research team led by José Silva and Jennifer Nichols of the Wellcome Trust Centre for Stem Cell Research in the UK examined the role of Nanog, a protein that was previously found to be a key player in the development of pluripotency. Nanog (its name taken from the Celtic 'Tir Nan Og' or 'land of the ever young') was obviously important, but its exact role remained unclear.

"Exactly how pluripotency comes about is a mystery. If we want to create efficient, safe and reliable ways of generating these cells for medical applications, we need to understand the process; our research provides additional clues as to how it occurs," said Dr Silva.

To resolve some of the paradoxes that arose from earlier studies, the researchers looked at mouse brain cells that did not have the Nanog-expressing gene. When they induced these cells to be reprogrammed, the cells started the process but became trapped in a kind of limbo, where they could not make the transition to pluripotency. When the researchers looked at the same types of cells that did have the Nanog-expressing gene, they observed that the cells were able to translate to full pluripotency.

"Other genes have been identified as acting in this process, but they act more as triggers," explained Dr Silva. "Then Nanog comes along. Without Nanog, cells are trapped in an undefined, intermediate step."

The researchers established that Nanog is indeed crucial but it comes in late in the process. Their observations indicated that the protein is required during the final phase of reprogramming, when other factors are already present and waiting. The study is the first to pinpoint the timing of Nanog action.

"Our research shows that this unique protein flips the last switch in a multi-step process that gives cells the very powerful property of pluripotency," explained Dr Silva. "We demonstrated that Nanog is absolutely required for the reprogramming of adult cells back into embryonic stem cells, and that this is true for embryonic cells as well."

The authors conclude that Nanog plays a central role in the crucial mechanism, somehow choreographing a network of genes and proteins to bring about pluripotency.

The next step for researchers is to unravel the complex interactions of all these factors to see exactly how Nanog influences these molecules to bring about pluripotency. Such knowledge will help scientists to create stem cells in the laboratory that could be used in the treatment of serious illnesses such as Alzheimer's and Parkinson's disease.

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