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While location, location, location has long been the mantra in real estate, it may soon become the buzzword of stem cell scientists everywhere. Weill Cornell researchers have discovered that bone marrow stem and progenitor cells immature cells that can give rise to all the cells of the blood and immune system must move to a specific location within the marrow to mature into blood cells that keep the body humming.

These immature cells get their instructions on how to grow and differentiate when they move into a blood-vessel enriched zone of the bone marrow known as the vascular niche. This movement, orchestrated by motility factors called chemokines, allows stem cells to differentiate into blood-clotting platelets and other blood cells.

The researchers have identified two motility factors that direct localization of stem cells to the vascular niche. These findings could one day benefit patients recovering from severe bone-marrow suppression due to drug treatments or illness. The results are published in the journal Nature Medicine (Vol. 10, 64-71, 2004).

The conventional wisdom was that proliferation and differentiation of stem cells are driven primarily by specific cytokines, which are growth factors that accelerate recovery of the blood counts after the patients are treated with chemotherapy and radiation, said Dr. Shahin Rafii, Professor of Medicine and Arthur B. Belfer Professor of Genetic Medicine at Weill Cornell Medical College.

However, cytokines are not very effective in the early phase of bone marrow suppression when a patient is susceptible to infection or bleeding because of extremely low blood counts, Dr. Rafii said. The new data suggest that factors that cause progenitor and stem cells to move from one location to another chemokines may be helpful when used in tandem with growth factors, or cytokines, which boost cell production. Currently, cytokines used to treat chemotherapy patients include erythropoietin (EPO) and granulocyte colony stimulating factor (G-CSF), which induce the production of red blood cells and white blood cells, respectively. These factors accelerate marrow recovery in the late stages of marrow suppression.

These new findings set forth the possibility that stem and progenitor active chemokines may facilitate blood cell recovery even in the early stages of marrow suppression, said Scott T. Avecilla, who is an MD-PhD student at Weil Cornell and the first author of this article. Such motility factors force rapid relocalization of stem and progenitor cells to the bone marrow's vascular niche, which can help restore blood counts in the initial, vulnerable phase of marrow suppression.

This new paradigm challenges the basic tenets of cytokine biology and introduces the novel concept that it is the physical localization, but not the absolute availability of cytokines, that determines the differentiation and maturation status of stem and progenitor cells. said Dr. Rafii, who is also Attending Physician at NewYork-Presbyterian Weill Cornell.

In a series of studies, Dr. Rafii and colleagues Scott T. Avecilla, Dr. David Lyden, Dr. David Jin, Koji Shido, and Rafael Tejada used two chemokines stromal derived factor-1 (SDF-1) and fibroblast growth factor-4 (FGF-4) to speed up the movement of stem cells from the bone marrow's resting location to the vascular niche. This relocalization was sufficient to induce rapid reconstitution of mature blood cells in animals with severely depressed bone marrow activity due to either drug treatment or a genetic deficiency.

Specifically, the researchers looked at a knock out mouse that lacks the capacity to produce a cytokine called thrombopoietin, which promotes the expansion of blood-clotting platelets. In these genetically-engineered mice, the number of platelets is decreased by 95%, but they produce enough platelets so they can survive without excessive bleeding. Treatment of the knock out mice with SDF-1 and FGF-4 boosted production of platelets to normal levels. Examination of the marrow showed formation of large numbers of platelet progenitors, which are cells referred to as megakaryocytes. The majority of the megakaryocytes were located within the vascular niche. When the researchers disrupted the vascular niche with an antibody against marrow blood vessels, it also blocked formation of megakaryocytes and reduced platelet production, suggesting that localization of progenitors to the vascular niche is essential for platelet production.

Moreover, the researchers were able to show that SDF-1 and FGF-4 used alone, or in combination, were highly effective in decreasing the magnitude and severity of marrow suppression after treatment with high doses of chemotherapeutic agents. We clearly showed that it's the chemokinetic activity of FGF-4 and SDF-1 that pushed the stem cells from the osteoblastic niche to the vascular niche and restored platelet production, Dr. Rafii said.

Everyone thought that stem cells randomly hang out in the bone marrow. Now we have defined several dynamic microenvironments within the bone marrow that dictate maturation and survival of stem and progenitor cells. There is the surface of the bone, the osteoblastic niche, which provides a safe haven for resting quiescent stem cells. Two years ago, we published a study (Cell Vol. 109, 627-637, 2002) demonstrating that under normal baseline physiological conditions stem cells hide or reside on the osteoblastic niche. In the current paper, we show that the stem cells move from the osteoblastic niche to the vascular niche, where they get instruction to differentiate said Dr. Rafii.

One other major finding is that, in contrast to cytokines such as EPO and G-CSF that can be delivered by injection, chemokines may have to be delivered intravenously. Dr. Ronald G. Crystal, Chairman of Genetic Medicine and Director of the Institute of Genetic Medicine at Weill Cornell, in collaboration with Dr. Rafii and Dr. Neil R. Hackett, is working on gene therapy approaches to deliver chemokines in a novel way. For example, harmless viruses expressing these chemokines may someday be used to deliver chemokines to patients continuously, thereby relieving them from daily painful and time-consuming infusions.

These studies are particularly important since clinical trials using recombinant thrombopoietin for treating chemotherapy-induced low platelet counts have confronted several obstacles. Specifically, recombinant thrombopoietin has been relatively ineffective in restoring platelet production in the initial phases of marrow suppression in patients who have received high doses of chemotherapeutic agents or have undergone bone marrow transplantation. While the researchers are planning on testing SDF-1 in a clinical trial in patients, they are proceeding with caution, said Dr. Rafii. One major hurdle is that stimulating and relocating stem cells may also spur the growth of tumor cells.

The downside is that if we give these chemokines to cancer patients, factors that mobilize stem cells, it may add fuel to the fire, said Dr. David Lyden who is Director of Cellular Oncology at the Children's Blood Foundation Laboratories at Weill Cornell. We showed that mobilization of stem cells to the circulation from the bone marrow can induce tumor angiogenesis [blood vessel formation] and growth. Therefore, introduction of high levels of these chemokines may promote tumor neo-angiogenesis and could become a double-edged sword.

In this regard, the researchers expect to identify specific chemokines that can be tailor-made for each individual blood factor. They hope that over time they can, for example, boost platelets in patients without affecting tumor growth in breast cancer or leukemia.

The present studies provide the platform for future pre-clinical and clinical trials to identify chemokines that will allow selective production of specific type of blood cells, such as platelets, white blood cells, or red blood cells, without recruiting stem and progenitor cells that may spur tumor growth, said Dr. Rafii.

Weill Cornell study co-authors include Scott T. Avecilla, Drs. Koichi Hattori and Beate Heissig, Rafael Tejada, Koji Shido, Dr. David Jin, Dr. Sergio Dias, Dr. Fan Zhang, Travis Hartman, Dr. Neil Hackett, Dr. Ronald G. Crystal, and Dr. David Lyden. Researchers from Genentech Inc and ImClone Systems also collaborated on the report.

The study was funded with grants from the National Heart, Lung, and Blood Institute, the American Cancer Society, the Leukemia and Lymphoma Society, the W.M. Keck Foundation, the Dr. Ezekiel Marion Foster Medical Scientist Fellowship, the National Institutes of Health, and the National Cancer Institute.