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New Research Promotes a More Dynamic View of Adult Stem Cell DifferentiationHematopoietic Stem Cells May One Day Be Used to Repair Tissue Damage Caused by Radiation Therapy or Chemotherapy by David Galloway
The classical model of the human cell system has cells traveling on a one-way street: An embryo is conceived, and embryonic stem cells grow into adult cells that form specific parts of the body, carry out their functions, and then die. Once a cell becomes a liver cell, for example, it remains a liver cell for the rest of its life. But recent research suggests a more dynamic picture, with cells constantly dying and being replaced by newly created cells of uncertain origin. It might even be possible for a liver cell to generate brain cells. “When I grew up, I was taught that neuronal cells were irreplaceable—if you lose them, you’ve lost them for life,” said Zeev Estrov, M.D., a professor in the Department of Bioimmunotherapy at The University of Texas M. D. Anderson Cancer Center. That belief is being challenged as researchers begin to unravel the mysteries of adult stem cells. “It’s so fascinating, if you really think it through—and this is all hypothetical—that our cell system and our body are much more dynamic than what we had thought,” said Martin Körbling, M.D., a professor in the Department of Blood and Marrow Transplantation at M. D. Anderson. In this dynamic model, the body is constantly repairing itself. For example, Dr. Estrov said, “If you walk outside today, and you stay out a little bit longer, then you can’t even describe what happens in your lungs. You inhale all the smoke and dust and toxins, and the body deals with it very successfully. When there is a failure in the system, you’ll be short of breath. It happens because the system has failed. But usually, for most people, the system is successful. There is damage and repair.” Most of this cycle of damage and repair occurs within individual cells. In some cases, however, large numbers of specific cells may be needed to repair tissues. Scientists have known for some time that certain adult stem cells, the hematopoietic progenitor cells, create red blood cells. Drs. Estrov and Körbling have researched using such cells to direct the repair of tissue damage.
In a study published in 2002 in the New England Journal of Medicine, they found that circulating stem cells could, as expected, differentiate into mature blood cells, but they could also become hepatocytes and epithelial cells of the skin and gastrointestinal tract. Other studies have shown potential benefits of adult stem cell treatment in repairing heart muscle damage due to infarction, in regenerating blood vessels to reverse ischemia in lower extremities, and even in repairing spinal cord injuries. Clinical studies are under way to investigate potential treatment strategies, including the repair of tissue damage caused by chemotherapy or radiation therapy by increasing the concentration of stem cells at the site of damage. This can be done either by injecting stem cells directly into the area where they are needed or by administering human granulocyte colony-stimulating factor systemically. The mechanisms of adult stem cell differentiation are not completely understood, but possible explanations for the differentiation of adult stem cells derived from bone marrow or corporeal blood into non-lymphohematopoietic tissue cells include the following:
Although none of these models has been proven, preclinical data support the transdifferentiation model. It is also possible, however, that more than one model may be at work simultaneously. Most adult hematopoietic stem cells reside in the bone marrow. Only about 0.1% of the body’s stem cells are circulating in the corporeal blood at any given time. These cells circulate to create homeostasis, ensuring that the percentage of stem cells in the marrow remains uniform among the more than 200 bones in the human body. For example, if the bone marrow in a patient’s leg is destroyed by radiation therapy, stem cells circulating in the corporeal blood will be delivered to the site of damage until the stem cell concentration in those bones increases to the same level found in the rest of the patient’s bones.
Both Dr. Estrov and Dr. Körbling said they were inspired by the work of Helen M. Blau, Ph.D., a professor in the Department of Microbiology and Immunology at the Stanford University School of Medicine. In the June 29, 2001, issue of Cell, Dr. Blau’s article titled “The Evolving Concept of a Stem Cell: Entity or Function?” put forth the hypothesis that a stem cell is defined less by what it is than by what it does. “So [Dr. Blau’s argument is that] any cell can acquire the stem cell function under certain conditions,” Dr. Körbling said. “Your skin cells can acquire the stem cell function and go back and produce something else. It’s a very, very dynamic understanding of the universe of stem cell biology.” One benefit for researchers using adult stem cells rather than embryonic stem cells is the avoidance of controversy. The political, ethical, and religious objections to embryonic stem cell research do not apply to the field of adult stem cells. According to Dr. Körbling, however, adult stem cell research cannot obviate the need for embryonic stem cell research. “An embryonic stem cell can differentiate into all three germ layers—mesoderm, ectoderm, and endoderm,” Dr. Körbling said. “This is the most totipotency you can imagine, but it is lost almost immediately. Whenever those cells are pushed into differentiation, this kind of potential is lost. And then we are into the adult stem cells.” Dr. Estrov agreed. “I think the breakthroughs in terms of understanding the mechanisms of differentiation are most likely to come from embryonic stem cell research,” he said. Dr. Estrov and Dr. Körbling believe that continuing discussions between ethicists and researchers are needed to establish common ground so that the study of embryonic stem cells can continue and people’s beliefs and convictions are respected. And both believe that future research using adult stem cells could open countless doors for scientists, clinicians, and patients. “If you think about the future applications of this, when you understand the mechanisms by which a cell from one tissue can be reprogrammed to become a cell of another tissue, then, in theory, you can take a cancer cell and reprogram it to be noncancerous,” Dr. Estrov said. “So it’s like every other field of medicine: You start from one field, and then you have implications for many, many other fields. It’s never limited.” For more information on this topic or for questions about M. D. Anderson’s treatments, programs, or services, call askMDAnderson at (877) MDA-6789. Other
articles in OncoLog, September 2003 issue:
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