'Fight or Flight' Reaction Importatnt in Getting Stem Cells into the Blood

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The Mount Sinai Hospital / Mount Sinai School of Medicine

Role of the nervous system in regulating stem cells discovered

Study led by Mount Sinai School of Medicine may provide new hope for

cancer patients and others with compromised immune systems

New study by Mount Sinai researchers may lead to improved stem cell

therapies for patients with compromised immune systems due to

intensive cancer therapy or autoimmune disease. The study is

published in this week's issue of Cell.

A group, led by Frenette, Associate Professor of Medicine at

Mount Sinai School of Medicine, found that the sympathetic--or " fight

or flight " branch--of the nervous system plays a critical role in

coaxing bone marrow stem cells into the bloodstream. Bone marrow

cells known as hematopoietic stem cells are the source for blood and

immune cells.

Hematopoietic stem cell transplants are now routinely used to restore

the immune systems of patients after intensive cancer therapy and for

treatment of other disorders of the blood and immune system,

according to the National Institutes of Health. While physicians once

retrieved the stem cells directly from bone marrow, doctors now

prefer to harvest donor cells that have been mobilized into

circulating blood.

In normal individuals, the continuous trafficking of the stem cells

between the bone marrow and blood fills empty or damaged niches and

contributes to the maintenance of normal blood cell formation,

according to the researchers. Although it has been known for many

years that the mobilization of hematopoietic stem cells can be

enhanced by multiple chemicals, the mechanisms that regulate this

critical process are largely unknown, they said.

One factor in particular, known as hematopoietic cytokine granulocyte-

colony stimulating factor (G-CSF), is widely used clinically to

elicit hematopoietic stem cell mobilization for life-saving bone

marrow transplantation, said Dr. Frenette.

Several years ago, Dr. Frenette's group reported that a second

compound, fucoidan, which is synthesized by certain seaweeds, could

also spur the stem cells into action. The group speculated that the

seaweed derivative might work by imitating a similar compound, called

sulfatide, naturally present in mammalian tissues.

To test the idea, the researchers examined mice lacking the enzyme

responsible for making sulfatide.

" Lo and behold, mice lacking the enzyme Cgt did not mobilize

hematopoietic stem cells at all when treated with the stimulating

factor G-CSF or fucoidan, " Dr. Frenette said. " You don't get such

dramatic results that often in science. We knew we had stumbled onto

something important. "

To their surprise, further study failed to connect the stalled stem

cell movement to sulfatide. Rather, they found, the deficiency

stemmed from a defect in the transmission of signals sent via the

sympathetic nervous system. The products of Cgt contribute to the

myelin sheath that coats and protects nerve cells, they explained.

Mice with other nervous system defects also exhibited a failure to

mobilize bone marrow stem cells, they found. Moreover, drugs that

stimulate the sympathetic nervous system restored stem cell movement

into the blood stream in mice with an impaired ability to respond to

norepinephrine, the signature chemical messenger of the sympathetic

system.

" The nervous system plays an important role in producing signals that

maintain the stem cell niche and retention in bone marrow, " Dr.

Frenette said.

" The new findings add another dimension of complexity to the

processes involved in stem cell maintenance and mobilization and

emphasize the interrelationships among the nervous, skeletal and

hematopoietic systems, " he added. " They all have to work together –

to talk to each other – to produce blood and maintain stem cells. "

The results suggest that differences in the sympathetic nervous

systems of stem cell donors may explain " conspicuous variability " in

the efficiency with which they mobilize hematopoietic cells into the

bloodstream, the researchers said. Furthermore, drugs that alter the

signals transmitted by the sympathetic nervous system to the stem

cells in bone may offer a novel strategy to improve stem cell

harvests for stem cell-based therapeutics, they added.

The unexpected findings by Frenette and his colleagues

further " suggest that the pharmacological manipulation of the

sympathetic nervous system may be a means of therapeutically

targeting the stem cells in their niche for the purpose of either

mobilization or, conversely, attracting stem cells to the niche

following transplantation, " they added.

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