Dec. 29, 2000 TORONTO - A team of researchers at The Hospital for Sick Children (HSC), led by geneticist John Dick, has discovered that distinct types of stem cells exist within the blood system that differ in the length of time that they can sustain a stem cell transplant. They have been termed short-term repopulating and long-term repopulating stem cells. The discovery of distinct types of stem cells with different functions has important clinical implications. This research is reported in the January issue of the scientific journal Nature Immunology.
The team developed a highly efficient method to transfer marker genes into the human stem cells and then track the function of the marked stem cells as they repopulated immune-deficient NOD/SCID mice. They found that some stem cells only functioned for the first month and then disappeared, while other stem cells only started to function after several months, but then persisted.
"The discovery of different classes of stem cells is significant because it gives us yet another clue on how the human blood system works," said Dr. Dick, a senior scientist in HSC's Cancer and Blood Research Program and a professor of Molecular and Medical Genetics at the University of Toronto (U of T). "Because the stem cells have different functions, the clinical use of these cells will also be different."
Stem cells make up just one in a million bone marrow cells, and are the cells from which the entire blood system grows. Stem cell transplants, a form of bone marrow transplants, are used widely for treating different types of cancer, anemia and auto-immune disorders. The potential for stem cell transplantation has exploded in recent years to include gene therapy for a variety of genetic disorders, the use of umbilical cord blood as a stem cell source for children, and stem cell expansion so a small stem cell source such as cord blood may be used for adult patients.
Most applications require that stem cells function for many years following transplantation. Therefore, the long-term repopulating stem cells would be the ones researchers would want to target when permanent replacement is important, such as in the development of new treatments, like gene therapy and stem cell expansion.
However, there may also be application for the short-term repopulating stem cells, which allow for a robust but temporary graft following a stem cell transplant. Cancer patients often have to undergo large doses of chemotherapy to eradicate tumours, however, this also wipes out the vast majority of the blood system, requiring a stem cell transplant to replace the damaged blood system as fast as possible. The short-term repopulating cells could play an important role in rapidly generating new blood cells until the long-term stem cells become more active. Future research will determine if a large number of these cells could be expanded in culture, leading possibly to more a more successful transplant.
The discovery of two different types of stem cells has made it important to determine how manipulations done to stem cells before transplantation might alter them and make them more or less effective. For example, this research has uncovered evidence that some culture conditions being developed for gene therapy purposes can reduce long-term repopulating stem cells, clearly an undesirable situation. Thus this new knowledge can be used to develop the most effective conditions for the type of stem cells that are needed for the specific application.
Stem cells are incredibly difficult to study as they look like most other blood cells under the microscope. The only way to tell the difference is to see them in action in a living organism as they produce bone marrow cells. In humans, the only time this is clearly visible is following stem cell transplantation. Given this, stem cell research involving humans is very difficult.
Dr. Dick's research team has developed over the last 10 years a system to reproduce the entire human blood system in mice. By transplanting human blood cells into special immune-deficient mice called NOD/SCID mice (which cannot reject the human cells), this system provides scientists with a methodology to study the development of the human blood system. This system has revolutionized the study of both normal and leukemic human blood systems and is used in many labs worldwide. It has aided the understanding of how stem cells function, how abnormalities arise in leukemia, and in the development of improved gene therapy and leukemia treatments. Dr. Dick's work in this area has been recognized with two important medical research awards: The 1997 Michael Smith Award from the Canadian Institutes of Health Research (CIHR), and the 2000 Robert L. Noble Prize from the National Cancer Institute of Canada.
The team involved in this study includes Dr. Guillermo Guenechea, a former HSC post-doctoral fellow, Dr. Olga Gan, HSC research associate, and Craig Dorrell, a U of T graduate student.
Funding for this research was provided by the CIHR, the NCIC with funds from the Canadian Cancer Society, and the Canadian Genetic Diseases Network of the National Centers of Excellence.
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