BioWorld International Correspondent

LONDON - A protein that damps down the division of stem cells in the skin could provide key information about how to stimulate stem cells to divide, and may play a role in some types of cancer.

Fiona Watt, deputy director of the Cancer Research UK Cambridge Research Institute in Cambridge, UK, told BioWorld International: "We have identified new properties of stem cells and found a protein, which we have shown controls the proliferation of stem cells. This is important for our understanding of both normal skin and a wide variety of cancers - not just skin cancers but cancers of the mouth, cervix and esophagus, too."

The work could lead to better ways of growing skin cells to treat burns and other injuries, as well as new therapies for some cancers.

Watt, working with scientist Kim Jensen, devised a new method of characterizing the markers on skin stem cells. A report of their study is published in the July 24, 2006, Proceedings of the National Academy of Sciences, "Single-cell expression profiling of human epidermal stem and transit-amplifying cells: Lrig1 is a regulator of stem cell quiescence".

The epidermis of the skin is constantly renewing itself, mainly through division of progeny cells from stem cells - but identifying the stem cells is very difficult. Jensen and Watt set out to find a different approach to characterizing markers for stem cells.

Previous studies looked at the expression of different genes in populations of stem cells. These populations were not "pure" populations, so it was difficult for researchers to spot patterns in gene expression.

Jensen took the approach of isolating cultured single cells from human epidermis, before taking the RNA from each cell and using it to generate a series of copy-DNA libraries. He then used a panel of known markers for stem cells to pick out the copy-DNA libraries that had come from stem cells.

"This meant we were not making a judgment in advance about whether or not a cell was a stem cell," Watt explained. "Once we had got the libraries and identified some of them as from stem cells, we then looked in these libraries for genes that were specifically expressed in stem cells."

The strategy paid off. The two researchers identified 14 genes that were more highly expressed in stem cells than in other cells from the epidermis.

One of those genes encoded a protein called Lrig1. "We thought that all the genes we identified were interesting, but we were particularly interested in this protein," Watt said, "because it is known to damp down the response of cells to a growth factor signal, so we guessed it played a role in keeping stem cells in a non-dividing state."

Jensen and Watt used antibodies to find out where in the skin Lrig1 was expressed. Their experiments confirmed that it was expressed by the same cells that they had previously identified as stem cells.

Overexpressing Lrig1 prevented cultures of epidermal stem cells from proliferating, they discovered. "But the most interesting result," Watt said, "was that when we knocked Lrig1 expression down in our cultures, we noticed a big increase in the number of stem cells."

That was good evidence that Lrig1 was controlling stem cell division, she added.

The pair carried out further investigations into the molecules that Lrig1 interacts with. "These studies suggested that one mechanism by which Lrig1 acts is by decreasing expression of a proto-oncogene called Myc, which is an important growth regulator in all cells," Watt said.

Earlier observations in Watt's laboratory fitted with this discovery: boosting the Myc expression in the skin, they had found, pushed the cells into differentiation.

"This led us to the hypothesis that when a cell loses Lrig1 expression, expression of Myc goes up. This might be a way of pushing the cells into an initial burst of proliferation, and they start to differentiate during steady state homeostasis of the epidermis," Watt said.

Interestingly, there have been reports that expression of Lrig1 is decreased in many tumors. "We want to explore this aspect in more detail," Watt said. "We would like to find out whether the levels of Lrig1 in a tumor give any clue to whether the patient will have a good outcome or a poor outcome."

Watt and Jensen also plan to use mouse models to find out whether stem cell proliferation in the epidermis is controlled by varying levels of Lrig1 expression.