Identification and characterization of an inhibitor of hematopoietic stem cell proliferation
Article Abstract:
The study of substances that inhibit cell proliferation is hampered by the fact that a great many substances will inhibit proliferation in a non-specific way, simply by virtue of their toxic effects. A new assay has been developed, however, to study the proliferation of primitive stem cells in bone marrow in tissue culture dishes. Stem cells are primitive cells that can reproduce and give rise to a variety of different descendent cells. Using this assay, a substance initially called SCI, or stem cell inhibitor, was identified. As the biochemical analysis of SCI continued, it became clear that SCI was identical with the macrophage inflammatory protein-1 alpha, or MIP-1 alpha. This substance is a highly specific inhibitor of stem cell proliferation, and has no effect on the replication of blood progenitor cells, which have already become committed to their adult role. Electrophoresis revealed that the molecule is about 8,000 daltons in molecular weight, but the active substance in tissue culture may exist in complexes that have higher molecular weight. Molecular cloning of the gene for MIP-1 alpha also resulted in the unexpected finding of a closely related substance, known as MIP-1 beta. This substance has no apparent effect on the stem cell colony-forming assay that was used to identify MIP-1 alpha. These findings demonstrate not only that the effect observed with MIP-1 alpha is highly specific, but also that these molecules may be a part of a larger family of molecules, which play a role in the regulation of hematopoiesis, or blood cell production. The inhibition of proliferating stem cells by MIP-1 alpha may have direct clinical importance. Since chemotherapeutic agents kill proliferating cells, whether they are normal or cancerous, the hematopoietic cells are often the first to take a beating during the treatment of cancer patients. Indeed, the toxicity of chemotherapeutic agents for these cells is one of the factors which limits the dosage of chemotherapy. If MIP-1 alpha could be used to temporarily inhibit stem cell proliferation, these cells would be removed from the list of potential targets for chemotherapy; not only would a serious side effect be reduced, but higher and possibly more effective doses of chemotherapy might then be administered. (Consumer Summary produced by Reliance Medical Information, Inc.)
Publication Name: Nature
Subject: Zoology and wildlife conservation
ISSN: 0028-0836
Year: 1990
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Growth factors: growth without inflation
Article Abstract:
The inhibition of cellular growth is an important part of the regulation of normal tissues. For example, new skin cells should be produced no faster than old cells are being lost, so that the appropriate number of skin cells is maintained. Under normal conditions, blood cells are replaced by the growth of progenitor cells, which have already been committed to their role in life. The stem cells, which are the very primitive cells that give rise to a host of different blood cells, remain quiescent. However, if a lot of blood is lost, these stem cells are rapidly recruited into the production of new blood cells to replace those lost. It has proved to be very difficult to study the inhibition of cell growth because of the lack of an appropriate assay. Much of such research is done with cell culture dishes, and a great many compounds inhibit cell growth for the simple reason that they are mildly toxic. How can one distinguish between toxic inhibition and inhibition which is physiologically normal? In the March 29, 1990 issue of Nature, researchers report the development of an assay for studying the inhibition of hematopoietic, or blood-producing, stem cells by adult macrophages, a particular type of blood cell. Using this assay the researchers were able to identify a compound called MIP-1 alpha, or macrophage inflammatory protein-1 alpha. This substance inhibits the proliferation of normal stem cells and may have enormous scientific and medical importance. One possible medical application might be reducing the side effects of chemotherapy. The chemical treatment of cancer destroys many cells simply because they are replicating, regardless of whether or not they are cancer cells. Because hematopoietic cells are always replicating, they are a constant target for chemotherapeutic drugs, and the destruction of these cells is one of the most serious side effects of chemotherapy. If a substance such as MIP-1 alpha could be used to suppress the hematopoietic cells for a short time, these cells might cease to be a target for chemotherapeutic drugs during treatment. Not only would a serious side effect be eliminated, but it might be possible to use higher and possibly more effective doses of the anti-cancer drugs. (Consumer Summary produced by Reliance Medical Information, Inc.)
Publication Name: Nature
Subject: Zoology and wildlife conservation
ISSN: 0028-0836
Year: 1990
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Megakaryocytic and erythrocytic lineages share specific transcription factors
Article Abstract:
One of the key problems facing modern biology is understanding the molecular events that take place during cell differentiation. During this process, a cell moves toward its adult role by turning off some genes and turning on others, causing the cell to become different from its sisters. Precisely how the cell manages to activate all the appropriate genes remains a mystery. In the case of the development of red blood cells, a particular factor has been identified that regulates the transcription of several genes, all relating to mature erythrocyte function. This factor has been termed GF-1 by some investigators, and variously NF-E1 and Eryf-1 by others. Research has now shown that this same factor is also present during the development of megakaryocytes, the bone marrow cells which give rise to the blood's platelets. Techniques of molecular biology demonstrate that in megakaryocytes, GF-1 activates the genes for proteins that are specific to platelet function, but not those specific for erythrocyte function. In the development of red blood cells, of course, this factor activates the appropriate erythrocyte genes. These findings indicate not only that GF-1 is common to these two different cell lineages, but also that other factors must be at work to distinguish these two cell types. There may be undiscovered molecules that repress the expression of erythrocyte genes in the megakaryocytes, or there might by novel methods of activation that permit a response to GF-1 by the erythrocyte genes of erythrocytes, but not those in megakaryocytes. (Consumer Summary produced by Reliance Medical Information, Inc.)
Publication Name: Nature
Subject: Zoology and wildlife conservation
ISSN: 0028-0836
Year: 1990
User Contributions:
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