BioWorld International Correspondent

LONDON - A trio of Spanish researches has identified a crucial factor that dictates how stem cells behave, and how proficient they are in their role of regenerating tissues.

The work of Maria Blasco, head of the molecular oncology department at the Spanish National Cancer Institute, and her colleagues pinpointed the length of the telomeres in the stem cells as an important determinant of their behavior.

Telomeres are the protective ends of chromosomes, often likened to the plastic tips that stop shoelaces from fraying. Those ends are comprised of repetitive stretches of DNA, and they are maintained by the telomerase enzyme. Eventually, however, the rate at which the telomeres degrade with every cell division outstrips the rate at which telomerase manages to maintain them - and at that point, the cell dies.

Blasco told BioWorld International: "Our work connects the field of telomeres and telomerase, which is accepted to have a role in cancer and aging, with the idea that stem cells also may play a role in cancer and aging. We have identified telomerase activity and telomere length as important regulators of stem cell behavior, which affect the ability of stem cells to regenerate tissues."

The study, by Blasco with Ignacio Flores and Maria Cayuela, also of the Spanish National Cancer Centre in Madrid, is reported in the July 21, 2005, issue of Science. The paper is titled "Effects of Telomerase and Telomere Length on Epidermal Stem Cell Behavior."

Blasco's laboratory has worked for years studying the role of telomerase and telomere length in cancer and aging. Her group was intrigued by the interlinked ideas that faulty stem cells could cause human diseases and that aging could be due to the loss of function of stem cells; and by the concept that there might be "cancer stem cells" - mutant stem cells capable of both regenerating the cancer and spreading it around the body.

Blasco and her colleagues decided to investigate what role telomerase levels and telomere length played in stem cell biology. "We felt it was important to know what makes stem cells behave in one way or another. If these cells are eventually going to be used to cure diseases, we have to be able to characterize them and know that they are going to behave in the way we expect," Blasco said.

For their study, the team used a method of labelling the stem cells present in the epidermis of the skin of mice, which allowed them to detect how many stem cells were present. They could also see, when they had given the mice a stimulus that would normally make the stem cells proliferate to produce new skin cells and hair follicles, how the cells of the mice were responding.

They then looked for differences in stem cell behavior in two strains of genetically modified mice. The first had been altered so that the epidermal stem cells had no telomerase, and therefore short telomeres. The second had higher levels of telomerase than normal in the epidermal stem cells.

In the first group, the stem cells were not activated and did not migrate to regenerate skin and hair tissue when given a stimulus that would normally cause them to proliferate and migrate. "In other words, when there was no telomerase, and the telomeres were short, the stem cells did not work properly to regenerate the skin and the hair," Blasco explained. "We think this could be a possible explanation for the loss of functionality of stem cells with aging."

By contrast, the stem cells in the second group of mice were "super-competent," Blasco said. "When we gave them the stimulus to divide, they regenerated the skin and hair much better than normal cells. But this was also associated with an increased ability of the skin to develop tumors."

The group now is going to look at whether stem cells lose their function in normal aging. The team also will use a range of mouse models for tumor suppressor genes and oncogenes to examine the effects of the mutations responsible on stem cell behavior.

"We also want to examine further the concept of the cancer stem cell,'" Blasco said, "to see how altering stem cells can have the consequence of increasing the risk of tumors."

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