Scientists Solve Stem-Cell Mystery
Learning their origin could open way to growing lots of them to fight diseases.

Published October 23, 2003
By Alan Bavley
Knight Ridder

Kansas City — Scientists at the Stowers Institute for Medical Research have taken important steps toward identifying
where blood-forming stem cells are nurtured in bone marrow, a discovery that has eluded researchers for a quarter-
century.

Their preliminary findings, and those of two other research centers, could help lead to ways to grow large numbers of
these cells in the laboratory and alter them genetically to improve the odds of patients with sickle cell anemia and
other diseases.

"This is basic research that you can translate into better human health," said Linheng Li, the biologist who led the
research team at Stowers in Kansas City. "How stem cell numbers are regulated in the body — that was unknown."

In separate studies using genetically engineered mice, the researchers at the 3-year-old Kansas City research campus
and a team of scientists from Harvard and the University of Rochester found evidence of what they believe is the
"niche," or biological environment, where blood-forming stem cells reside in bone marrow.

These hematopoietic stem cells are tied closely to a certain type of bone-forming cells called osteoblasts in bone
marrow, both research groups reported.

Using different techniques, the researchers were able to increase the number of osteoblasts that make up the niche
areas in the mice, more than doubling the number of stem cells.

Studies by the two groups are being published today in the journal Nature.

"We always knew that the fertile ground for blood-cell production was in the center of the bones, but we've had very
little understanding of the maintenance of these (stem) cells," said John DiPersio, director of the bone marrow
transplantation program at Washington University in St. Louis.

"This research allows us to begin to explain the obvious relationship between bone and bone marrow that we have ignored
in the past."

Stem cells have become a central focus of biological research because they can reproduce almost indefinitely and be
turned into the diverse kinds of cells that make up the body.

In embryos, stem cells develop into all the different tissues of the body. Fully grown organisms retain more
specialized stem cells that replenish the blood, skin and other tissues.

Scientists hold out hopes of devising numerous applications for stem cells — from replacing the destroyed brain cells
of Parkinson's disease patients to providing new insulin-producing cells to diabetics.

Doctors have long used transplants of hematopoietic stem cells to replace the blood-making system in patients with
leukemia and some other cancers and blood disorders.

Most transplants have used bone marrow from donors, but in recent years doctors more frequently have used stem cells
extracted from donors' blood.

Patients undergo radiation or chemotherapy to kill their own bone marrow before receiving injections of stem cells from
a donor. The cells migrate to the bones and resume making blood.

If scientists were able to grow adequate supplies of blood-forming stem cells in the laboratory, they could be put to
additional uses, DiPersio suggested.

There is evidence that patients are less likely to reject stem cells harvested from blood contained in discarded
umbilical cords. So far, cord blood stem-cell transplants have been given to children, because doctors haven't been
able to extract enough stem cells to use in adults.

But if stem cells from umbilical cord blood could be grown in the laboratory, they could be used to treat leukemia and
other diseases in adults, DiPersio said.

Growing blood-forming stem cells in the laboratory also would give scientists the opportunity to modify them
genetically as potential treatments for inherited diseases.

That kind of research has been hindered because stem cells rapidly turn into blood cells once they are isolated in the
laboratory.

"Right now, we have very poor ways to put genes into stem cells," DiPersio said. "It's a really inefficient process."

Scientists first suggested in 1978 that a stable niche environment might control hematopoietic stem cells, but they had
been unable to identify it. Without a clear knowledge of how these stem cells were maintained by the body, scientists
have found it difficult to grow the cells in the laboratory.

The Stowers researchers discovered that the stem cells congregate in trabecular bone, the rigid but spongy-looking bone
found in the spine, pelvis and inside the ends of long bones such as the femur, or thigh bone.

Li manipulated genetically engineered mice to produce extra trabecular areas in their femurs. The more trabecular area,
the more blood-forming stem cells the mice had.

The researchers then homed in on those areas. They found that the stem cells clung to a particular type of spindle-
shaped osteoblastic cell that lined the interior of trabecular areas.

"It makes sense," Li said. "Bone marrow depends on bone; somehow, the two have to be coordinated."

The researchers also found a chemical on the surfaces of the osteoblasts and stem cells that may help the cells adhere
to one another.

Collaborating with the Stowers researchers were scientists from the University of Missouri-Kansas City School of
Dentistry and the National Institute of Environmental Health Sciences, in Research Triangle Park, N.C.

The Harvard and University of Rochester group used genetically engineered mice that produced a large number of
osteoblasts. They found that as the number of osteoblasts in the mice increased, so did the number of blood-forming
stem cells.

SOURCE: The Springfield News Leader, MO
http://www.news-leader.com/today/1023-Scientists-199461.html

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