Bone marrow transplantation is a last-resort treatment that saves the lives of many patients with cancer and inherited blood disorders. In a transplantation, the patient's malignant or defective stem cells in the marrow are destroyed, and healthy stem cells are transfused intravenously into the circulation. To obtain the healthy stem cells - either from a healthy donor or from the patient himself before or during treatment with chemotherapy - these cells must be "encouraged" to come out of the marrow into the bloodstream (in other words, they must be "mobilized"). Thus, scientists have been trying to find out what triggers stem cell mobilization.
Dr. Tsvee Lapidot of the Institute's Immunology Department, and his Ph.D student, Isabelle Petit, found that the degradation of SDF-1, a key protein in the bone marrow, is crucial for stem cell mobilization. SDF-1 had previously been found by this and other research teams worldwide to anchor stem cells inside the marrow by activating adhesion molecules (molecules that serve as "glue"). Uncovered today is the "anchors aweigh" mechanism that frees stem cells into the blood.
The scientists investigated stimulation with the growth factor G-CSF, currently the most common clinical method used to induce stem cell mobilization (in addition to its role in bone marrow transplantation, it is also used to treat children suffering from neutropenia, i.e lack of white blood cells in the circulation). Before this study, G-CSF's mode of action was largely unknown. Lapidot and Petit found that it reduces the number of SDF-1 proteins in the marrow. It does this by causing the production of degrading enzymes, in particular elastase. The result: stem cells attached to the marrow lose their "anchors" and flow into the bloodstream. Stem cells produced during SDF-1 degradation will not be able to cast anchor to begin with and will also exit the marrow. The scientists found that stem cell mobilization peaked when SDF-1 levels in the bone marrow were at their lowest.
In addition, the team observed another of G-CSF's effects: it causes an increase in the number of receptors of a certain type (called CXCR4) on stem cells and maturing white blood cells in the bone marrow. CXCR4 is the receptor that binds specifically with SDF-1. Surprisingly, they found that interactions between SDF-1 and CXCR4 are necessary for mobilization to take place. Inhibition of SDF-1 and CXCR4 interactions with neutralizing antibodies blocked stem cell mobilization.
The findings may lead to improved collection of stem cells for clinical transplantations. It also sheds new light on neutropenia, resulting from a genetic defect in the elastase enzyme, which the group found plays a central role in degrading SDF-1. An experimental system for human stem cells developed by Dr. Lapidot and his colleagues in 1999 enables studying the mechanism by which human blood forming stem cells migrate from the blood into the bone marrow by transplanting human stem cells into immunodeficient mice, which lack the ability to reject foreign cells. In the current study this model was used to reveal the mechanism of human stem cell mobilization in these mice. Part of the study was also conducted with samples obtained from healthy donors treated with G-CSF for clinical stem cell transplantation.
Donor Support: The M.D. Moross Institute for Cancer Research, Gabrielle Rich Center for Transplantation Biology Research, the Levine Institute of Applied Science, Mr. Clifton S. Robbins, New York, NY., the Naftali Foundation, Israel, Concern Foundation, Beverly Hills, CA., Ms. Nora Peisner, Hungtington, MI., and Ms. Rhoda Goldstein, Nanuet, NY.
The Weizmann Institute of Science is a major center of scientific research Israel. Its 2,500 scientists, students and support staff are engaged in more than 1,000 research projects across the spectrum of contemporary science.