Scientists find key to stem cell youth

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Scientists find key to stem cell youth

http://news-service.stanford.edu/news/2003/april30/scientists.html

By AMY ADAMS

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

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. This fat turns out to be critical for the Wnt

proteins to function properly in the cell.

With a Wnt in hand, researchers could finally confirm previous hints

that the protein helps stem cells maintain their youthful state. This

work, done in collaboration with 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 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.

The researchers 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.