Feb. 8, 1999 REHOVOT, Israel --February 5, 1999 -- In bone marrow transplantation, a patient receives a transfusion of stem cells, which migrate to the patient's bone marrow and start producing new, healthy blood. But many transplants fail because, usually, very few stemcells make their way from the blood circulation into the recipient's marrow.
In a study published in the February 5 issue of Science, a research team headed by Dr. Tsvee Lapidot of Weizmann Institute's Immunology Department has revealed key elements of the mechanism responsible for stem cell migration from circulating blood to the the bone marrow. Furthermore, the scientists managed to dramatically increase the proportion of stem cells capable of migrating to the marrow. The research was conducted in immunodeficient mice transplanted with human stem cells.
"In the future, this approach might improve the success rate of human bone marrow transplantation," Dr. Lapidot says. He conducted this research with his team members Drs. Amnon Peled, Isabelle Petit and Orit Kollet, and departmental colleagues Drs. Ofer Lider and Ronen Alon, together with Prof. Dov Zipori of the Molecular Cell Biology Department.
Bone marrow transplantation is a last-resort treatment that saves the lives of many patients with leukemia and other malignancies and blood disorders. In a transplantation, the patient's malignant or defective marrow is destroyed, and healthy stem cells are transfused intravenously into the circulation in the hope that they will find their way to the patients bones and create normal marrow. This marrow tissue daily produces hundreds of billions of blood cells, including both red blood cells, and white blood cells which protect the body from infections as part of the immune response.
No Receptor - No Migration
The Weizmann Institute scientists found that only human stem cells equipped with a certain type of receptor, called CXCR4, migrated from the circulation to the bone marrow of experimental mice. Thanks to this receptor, the cells were able to migrate to an "attracting" signaling molecule called SDF-1, which is released by bone marrow cells. It is this molecular "attractor" which guides human stem cells through the blood vessel walls into the marrow cavities.
"We discovered that human stem cells are sort of like sailboats," Lapidot says. "A sailboat will pick up the wind only if its sail is put up on the mast; similarly, stem cells will migrate to the bone marrow only if they display a specific receptor on their surface that allows them to pick up the signals from marrow cells."
The researchers found, however, that only a small number of human stem cells display the CXCR4 receptor on their surface, a fact that explains why so few stem cells are successfully transplanted - patients typically wind up with only 10% of the normal number of these cells. In the past, this low success rate was attributed to what was believed to be rapid stem cell differentiation. According to this theory, stem cells that entered the marrow cavity "disappeared" because, instead of proliferating, they quickly matured into various types of blood cells. The new study, however, suggests that stem cells may also "disappear" because they lack the CXCR4 receptor and therefore fail to migrate to the recipient's marrow.
Treating Cells Results in Improved Migration
The researchers further demonstrated that the majority of human stem cells that do not express the CXCR4 receptor on their surface have the potential to do so. When, prior to transplantation, the stem cells were treated in a test tube with natural growth factors that stimulated them to express the CXCR4 recetor, they were converted into migrating cells capable of contributing to the daily blood production. In the Weizmann study, this technique increased the number of successfully transplanted, funtional human stem cells from 25 percent to greater than 90 percent.
In the future, it may be possible to predict the success of a bone marrow transplantation by evaluating the highly variable proportion of the patient's stem cells that express the CXCR4 receptor. Furthermore, it may even be possible to pre-select the stem cells equipped with the CXCR4 receptor for transplantation purposes, or to pre-treat the stem cells so that they all display the recptor. These measures should significantly increase the numbers of stem cells transplanted into the patient's bone marrow, and therefore the overall success rate of the procedure . Clinical testing of the method is currently under consideration.
This study could be conducted thanks to an experimental system developed by Dr. Lapidot and his colleagues, which overcomes a major difficulty in studying human stem cells - the fact that in a test tube, they quickly differentiate into mature blood cells and disappear. Lapidot's team developed a way of studying human stem cells by transplanting them into immunodeficient mice, which lack the ability to reject foreign cells. This animal model thus serves as a powerful tool for research that may lead to improved therapies for human leukemias and other disorders.
The study was conducted in collaboration with researchers and physicians from Israel's Hadassah University Hospital in Jerusalem, Kaplan Medical Center in Rehovot, and Sourasky Medical Center in Tel Aviv, and from the Jackson Laboratory of Bar Harbor, Maine.
Yeda Research and Development Co. Ltd., the Weizmann Institute's technology transfer arm, has filed a patent application for the findings of Lapidot's team.
Dr. Lapidot holds the Pauline Recanati Career Development Chair of Immunology. The research was supported by grants from the Israel Academy of Sciences and Humanities, the Israel Cancer Research Fund, the Minerva Foundation of Munich, Germany, the Balfour Pelsner Bone Marrow Cancer Research Fund and the Israel Ministry of Science.
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