Aug. 2, 1999 REHOVOT, Israel -- Weizmann Institute researchers have developed a molecule that allows blood stem cells -the body's most primitive, immature cells that originate in the bone marrow - to multiply without differentiation in the test tube.
This achievement, described in the August issue of the journal Blood, may improve bone marrow transplantation, in which stem cells are infused into a patient to replace defective or malignant marrow. The study may also advance gene therapy research.
The new molecule was developed by Prof. Michel Revel and Dr. Judith Chebath of the Molecular Genetics Department, and its effects on blood stem cells were studied by Dr Tsvee Lapidot and graduate students Orit Kollet and Ronit Aviram of the Immunology Department.
Most stem cells originating in the bone marrow mature on a daily basis to supply our blood with the differentiated blood and immune cells that it needs. A small number of stem cells, however, survive and renew themselves without differentiation thanks to a natural mechanism by which the cells receive signals from molecules called cytokines. Among these cytokines is interleukin-6, a chemical messenger discovered in the 1980s in Revel's laboratory. In order to respond properly to interleukin-6, the stem cells have to form on their surface a multimolecular cluster which binds this cytokine. The cluster consists of a receptor molecule known as gp130 on the surface of the stem cell, and another molecule called the interleukin-6 receptor, which the cells pick up from surrounding fluids.
In contrast, when isolated in the test tube, the stem cells do not efficiently form the receptor cluster which binds interleukin-6 and fail to survive. They start to mature into various types of blood cells and lose their original properties within three to five days. The short survival time of stem cells in culture, has caused great difficulties in studying stem cells and using them for therapeutic purposes.
In their study, Weizmann Institute scientists used a so-called - chimera - recombinant molecule, consisting of interleukin-6 and its receptor fused together. The - chimera - molecule proved very efficient in forming a cluster with the gp130 receptor. When the chimera was added together with other cytokines to isolated stem cells, the cells were able to survive in the test tube for two weeks, and their numbers increased significantly. In the future, this new approach may make it possible to keep the stem cells, purified from human bone marrow or from human umbilical cord blood, proliferating without maturation for much longer.
When the treated human stem cells were transplanted to mice with severe combined immunodeficency, they successfully repopulated the bone marrow and differentiated into all the various types of blood cells, demonstrating that the stem cells had indeed remained immature. A large increase in the efficacy of transplantation was observed with the stem cells that had received the chimera treatment compared with cells treated with other cytokines.
If the Weizmann Institute molecule is adopted for clinical use, stem cells can be preserved for longer periods of time, their numbers can be greatly increased, and the success of bone marrow transplantation can be improved. Such transplantation is currently used to treat an increasing number of diseases, including different types of leukemia and cancerous tumors, several blood cell disorders and even autoimmune diseases such as multiple sclerosis.
The Institute study may also provide a boost to gene therapy research by giving scientists a larger window of opportunity for inserting genes into human stem cells maintained in the laboratory. The increased efficiency of gene transfer into stem cells may enable scientists to achieve greater success in developing gene therapy for various genetic disorders such as thalassemia, severe combined immunodeficiency, Gaucher?s or other diseases. When the transplanted stem cells repopulate the bone marrow of the recipient and mature into billions of blood cells, inserting a gene in these cells prior to transplantation would ensure a steady supply of the protein made by this gene. This may be used to compensate for various disease-causing genetic defects.
The Institute scientists collaborated with researchers from the Bone Marrow Transplantation Center at the Hadassah University Hospital in Jerusalem, from the Kaplan Hospital in Rehovot and the Jackson Laboratory, Bar Harbor, Maine, United States.
Prof. Revel holds the Ruth & Jerome A. Siegel and Freda & Edward M. Siegel Chair of Virology, and Dr. Lapidot, the Pauline Recanati Career Development Chair of Immunology. The study was supported in part by The Ares-Serono Group, the Israel Academy of Science, the Balfur Peisner Bone Marrow Cancer Research Fund, the Minerva Foundation, Munich, Germany, and the National Institutes of Health, U.S.
The Weizmann Institute of Science, in Rehovot, Israel, is one of the world's foremost centers of scientific research and graduate study. Its 2,500 scientists, technicians, and engineers pursue basic research in the quest for the enhancement of the human condition. New ways of fighting disease and hunger, protecting the environment, and harnessing alternative sources of energy are the Weizmann Institute's highest priorities.
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