Study may provide new hope for cancer patients

Jan 27 2006

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 Paul 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.