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Study identifies molecule essential
for proper localization of blood stem cells
Result supports interaction between
bone formation and production of blood, immune cells
BOSTON - January 13, 2006 - Scientists at the Massachusetts
General Hospital (MGH) Center
for Regenerative Medicine and the Harvard
Stem Cell Institute (HCSI) have defined a molecule that dictates
how blood stem cells travel to the bone marrow and establish blood
and immune cell production. The discovery may help improve bone
marrow stem cell transplantation and the treatment of several blood
disorders.
"This is another remarkable example of how bone and bone marrow
interact. A receptor known to participate in the body's regulation
of calcium and bone also is critical for stem cells to engraft in
the bone marrow and regenerate blood and immune cells," says
David Scadden, MD, director of the MGH Center for Regenerative Medicine
and co-director of the HSCI. "It reminds us how tissues interact
and how looking closely at where stem cells reside may tell us a
lot about how to manipulate them." Scadden is senior author
of the report, which will be published in the journal Nature
and has received early
online release.
Hematopoietic or blood stem cells are critical to the daily production
of over 10 billion blood cells and are the basis for bone marrow
transplant therapy for cancer. Rare and difficult to identify, these
cells are extremely powerful at regenerating blood and immune cells
but only if they travel to the proper location when introduced into
the body. Typically the cells are infused into a vein, and they
find their way to the bone marrow through a process that depends
on largely unknown molecules.
Within the bone marrow cavity, stem cells are usually found in the
outer layer close to the inner surface of the bone. Since the process
of remodeling bone takes place in the adjacent bone tissue and because
studies by Scadden's group and others have shown that bone-forming
osteoblast cells are essential to the regulation of the stem cell
environment, it seemed probable that fundamental interactions exist
between the processes of bone formation and stem cell development.
As increased extracellular calcium is required for bone formation,
the researchers theorized that a molecule called the calcium-sensing
receptor (CaR), present on many cells, might be key to the localization
of blood stem cells.
To test their theory, the researchers first verified the presence
of CaR on primitive marrow cells taken from normal mice. They then
ran several experiments using transgenic mice that do not produce
the CaR protein and found that, while many types of marrow and adjacent
bone cells were present in normal proportions, levels of blood stem
cells were very low in the marrow cavities of the transgenic mice.
Other experiments showed that the absence of other cell-surface
molecules did not affect the numbers of stem cells in the marrow.
Examination of the spleens and the blood of the transgenic mice
showed that the numbers of primitive blood stem cells were significantly
elevated in those areas, indicating that the absence of CaR did
not affect the production of stem cells by the fetal liver. In a
group of normal mice that received radiation at doses that would
destroy the bone marrow, transplantation of fetal liver cells from
mice with and without CaR allowed the animals to survive, but those
who received cells from CaR-negative mice had dramatically fewer
stem cells in their bone marrow. Additional experiments showed that
the CaR-negative cells were unable to adhere to collagen I, an essential
bone protein produced by the osteoblasts.
"Since there are already drugs available that target this receptor,
we may be able to quickly adapt these findings in animals to the
treatment of human patients," says Scadden, who is a professor
of Medicine at Harvard Medical School.
Lead author of the Nature report is Gregor Adams, PhD, of
the Center for Regenerative Medicine and HSCI; a group of collaborators
from Brigham and Women's Hospital (BWH) was led by Edward Brown,
MD. Other co-authors are Karissa Chabner, Ian Alley, Dougas Olson,
Zbigniew Szczpiorkowski, MD, and Mark Poznansky, MD, PhD, of the
MGH; and Claudine Kos, PhD, and Martin Pollack of BWH. The research
was supported by grants from the American Society of Hematology,
the Burroughs Wellcome Fund, the Doris Duke Charitable Trust and
the National Institutes of Health.
Massachusetts General Hospital, established in 1811, is the original
and largest teaching hospital of Harvard Medical School. The MGH
conducts the largest hospital-based research program in the United
States, with an annual research budget of nearly $500 million and
major research centers in AIDS, cardiovascular research, cancer,
cutaneous biology, medical imaging, neurodegenerative disorders,
transplantation biology and photomedicine. In 1994, MGH and Brigham
and Women's Hospital joined to form Partners HealthCare System,
an integrated health care delivery system comprising the two academic
medical centers, specialty and community hospitals, a network of
physician groups, and nonacute and home health services.
Media Contact: Sue
McGreevey, MGH Public Affairs
Physician Referral Service: 1-800-388-4644
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