4/27/03 News Release

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STANFORD, Calif. ­ Scientists have finally laid hands on the first member of a recalcitrant group of proteins called the Wnts two decades after their discovery. Important regulators of animal development, these proteins were suspected to have a role in keeping stem cells in their youthful, undifferentiated state - a suspicion that has proven correct, according to research carried out in two laboratories at Stanford University Medical Center. The ability to isolate Wnt proteins could help researchers grow some types of stem cells for use in bone marrow transplants or other therapies.

The gene coding for a protein usually reveals clues about how that protein will react in the lab and how best to isolate it from other molecules. The Wnts are unusual, however, because the way they behave in the lab differs from what the gene suggests. Roeland Nusse, PhD, professor of developmental biology at the School of Medicine and one of the first to isolate a Wnt (pronounced "wint") gene, reports how his lab members overcame these hurdles in the April 27 advance online edition of the journal Nature.

"We found that the protein is modified, explaining why it has been difficult to isolate," said Nusse, who is also an investigator at the Howard Hughes Medical Institute. Although the protein's structure suggests it should dissolve easily in water, Karl Willert, PhD, a postdoctoral fellow in Nusse's lab, found that an attached fat molecule makes the protein shun water and prefer the company of detergents instead.

With a Wnt in hand, researchers could finally confirm previous hints that the protein helps stem cells maintain their youthful state. This work, led by Irving Weissman, MD, the Karel and Avice Beekhuis Professor of Cancer Biology, involved cells in the bone marrow called hematopoietic stem cells that generate all blood cells throughout a person's life. When these cells divide, some offspring go on to become red blood cells, immune cells and other blood components, while other offspring continue the stem cell line.

Experiments carried out by Tannishtha Reya, PhD, a former postdoctoral fellow in Weissman's lab and now at Duke University, and graduate student Andrew Duncan showed that Wnt protein could cause hematopoietic stem cells to divide. After a week in an environment containing Wnt, mouse hematopoietic stem cells were about six times more likely to be dividing than cells grown in control conditions. What's more, the majority of cells in the Wnt-containing environment were still stem cells, whereas their counterparts had blossomed into a potpourri of other blood cell types.

Additional experiments by Reya showed that other components of the Wnt pathway also trigger stem cell growth and that the pathway is required for stem cell maintenance. Reya describes these studies in a second Nature paper published alongside Nusse's work.

"It's a big deal to understand how these hematopoietic stem cells expand their numbers," Weissman said. With the ability to grow more stem cells in the lab, researchers would have a pool of cells available for research or potential therapies. Many molecules called growth factors cause stem cells to divide, but the new cells all go on to become other blood cell types.

"Whenever we would add these growth factors, at the end of the day we would have many different types of blood cells but no more stem cells than we started with," Weissman said.

The ability to grow hematopoietic stem cells would help doctors who need large numbers of these cells for use in bone marrow transplants. In Nusse's paper, the researchers led by Reya reported that mouse hematopoietic stem cells grown in the presence of Wnt were better able to replenish the bone marrow of transplant recipients than stem cells grown without the protein.

In addition to the effects on hematopoietic stem cells, members of the Wnt family of proteins may nudge stem cells from other tissues to divide, making them easier to use in potential therapies. What's more, knowing how stem cells self-renew could lead to ways of blocking self-renewal in the cancer stem cells that populate tumors. "We are now actively looking at whether any mouse or human cancers are using the Wnt pathway," Weissman said.

Additional Stanford researchers who participated in the work include Jeff Brown, PhD, a postdoctoral fellow; Esther Danenberg, a technician; and Laurie Ailles, a graduate student.

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