Stem Cell Therapy

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By Gregg Clark, Ph.D.

What are stem cells?
Stem cells are cells in the body that continually renew themselves by producing daughter cells. Some of these daughter cells go on to change and become cells that are specific to different tissues in the body. So stem cells are the source cells from which all other cells in our body come from. Their ability to give rise to a variety of different types of cells (e.g. lung, heart, skin, retina, etc.) is what makes them so valuable to the biomedical world today.

Are they all the same?
No. There is a variety of stem cells that are in our bodies that give rise to various tissue specific cells. Some can give rise to more tissue cell types than others and that is actively being studied in labs around the world. The stem cells present in our bodies are known as adult stem cells while another type of stem cell also can be found in developing embryos of animals and humans. These are called embryonic stem cells. These can be isolated from embryos only days after fertilization of the egg occurs. They are easier to isolate in large numbers relative to adult stem cells and tend to give rise to a greater number of cell types than do adult stem cells. Their ability to develop into a wide variety of cell types is a key reason for the current enhanced interest in studying their biology.

There has been much discussion over the ethics of human embryonic stem cell research and I will not touch on that topic here, as I want only to explain the scientific basis of stem cell research so you have a better understanding of what it involves. While embryonic stem cell research is a hot political topic, much is being done with adult stem cell research/ therapy that is quite exciting.

Why are they important?
Because they are able to give rise to a variety of new cell types, stem cell use in tissue regeneration is of great potential. The idea would be to replace damaged tissues by the addition of stem cells that then would grow and generate new undamaged tissue, for example, in the brain or heart. In almost any situation where tissue damage has occurred, stem cell therapy could be applied. This potential has caused great excitement in the field of medicine, as well as other fields.

Do they have therapeutic uses?
Yes they certainly do. For years now people with leukemia and other blood diseases have been getting bone marrow transplants for successful treatment of their disease. The bone marrow is the source of stem cells that give rise to new blood cells to replace the diseased ones in a patient. And now, new uses are being tested in animal models and in some cases with humans that go beyond the treatment of blood diseases alone. In addition, cord blood cells isolated from the umbilical cords of newborn babies are also a richsource of blood stem cells and have been used in treatment of various blood diseases. New uses of these cells are also being tested for treatment of disease other than that of the blood.

Stem cell applications
I would like to talk about stem cell application in the areas of heart disease, diabetes, arthritis, brain disease, and eye applications. Then I will briefly discuss some of their limitations and future directions of the research.

Heart disease
Studies have been performed with mice that have had induced heart attacks and then received bone marrow-derived cells by direct injection into the heart. Cardiac function improved in those mice receiving the bone marrow cells, implying that the cells were able to help aid heart function in some way. The exact reason for this improvement is still a matter of discussion, but the results have encouraged doctors to test for such effects in humans. In one trial, some patients who had suffered acute myocardial infarction and had been treated with angioplasty were treated with bone marrow-derived or blood-derived stem cells by intracoronary injection. In 20 patients there was an improvement in heart function (left ventricular function) regardless of the type of stem cell they received. This has been repeated in several different trials with similar results and few side effects have been observed. The actual mechanism behind the improvement remains to be determined, but with larger trials and continued study this should be discovered eventually. For a review on this subject see: Lee, M.S. and Makkar, R.R. 2004. Stem-Cell Transplantation in Myocardial Infarction: A Status Report. Annals of Internal Medicine, vol. 140, pp. 729-737.

Diabetes
In another application of stem cell therapy for a disease state, diabetic rats have been injected with embryonic stem cells that express insulin. Improvement in glucose control was observed. Transplantation of bone marrow-derived cells were found to normalize glucose and insulin levels in diabetic mice and their survival rate was better. Studies are ongoing to further define the fate of donor bone marrow cells. There is also an autoimmune component to diabetes that complicates treatment success, but that is under investigation. For a review see: Hussain, M.A. and Thiese, N.D. Stem-cell therapy for diabetes mellitus. 2004 Lancet, vol. 364 (July 10), pp. 203-205.

Arthritis
I attended a seminar recently, where scientists at the University of Florida are trying stem cell therapy to treat arthritis in animal models. They are hoping to relieve inflammation and to be able to develop new cartilage in affected joints with this treatment. The work is in the beginning stages, but it is promising.

Brain Disease
Embryonic stem cells and adult brain stem cells have been shown to possess plasticity with their ability to convert to different cell types in the lab. Continued research into the control of this conversion is ongoing for use in cell transplant applications for diseases like Parkinson's. In this situation dopamine production in the brain has declined and the idea would be to enhance it through the addition of new functional dopamine producing brain cells. Although adult brain cells have been found in both rodents and humans, their numbers are small but potentially very powerful in their potential for treatment of neurological disease. Also the application of bone marrow stem cells in mice with a Parkinson-like disease has showed encouraging results. For a review in this area of research see: Rice, C.M., Halfpenny, C.A. and Scolding, N.J. 2003. Stem cells for the treatment of neurological disease. Transfusion Medicine, vol. 13, pp. 351-361.

Treatment of stroke using human bone marrow derived stem cells is another application that is showing promise in animal models. In addition, just recently a report has come out that human cord blood specific cells can promote the growth of blood vessels in the areas of brain damage in mice with induced stroke. This treatment may promote brain cell regeneration through the development of new blood vessels and the recruitment of brain stem cells to the injury site. This was taken from: Taguchi, A. et al. Administration of CD34+ cells after stroke enhances neurogenesis via angiogenesis in a mouse model. 2003. The Journal of Clinical Investigation, vol. 114, Number 3 August, pp 330-338

Eye Applications
Progress is being made in the area of treating retinal diseases with stem cell therapy, but the task is a little more complicated because of the variety of cells that make up the retina. The retina is a multi-layered tissue that consists of about 7 classes of cells with some 50 different types making up those classes. These classes appear at different times during embryo development and are fitted together in a specific pattern to give a functioning retina. For stem cell therapy to be effective for the retina, the cells will have to find their way into the retina and develop into the correct cell type. Experiments where brain stem cells from rats were injected into the vitreous of adult rat eyes resulted in migration and incorporation of the cells into the rat retina. Unfortunately, development of retinal cell characteristics did not occur. However, more recently mammalian retinal stem cells have been isolated and tested in a similar way and they do seem to be able to incorporate and to develop into retinal cells. This is work that has been done by groups at Harvard, Iowa State University and Children's Hospital of Orange County, California.

This fall a report was published by a group from the Scripps Institute in San Diego that tested bone marrow stem cell therapy on mice with degenerating retinas. They found that when bone marrow cells from human or mouse origin were injected into the vitreous of the defective mice, a stop in retina cell degeneration was observed and new cells were generated. In this case the stem cells may have helped preserve important blood vessels that led to an enhancement in retinal cell generation. Some functional activity of the retina via electroretinogram recordings was observed although they were abnormal. However, these results are very exciting in their application perhaps to slowing retinal degeneration in diseases like retinitis pigmentosum. Another potential application of this type would be to target stem cells to the retina to prevent formation of unwanted blood vessels in eye diseases where this is a problem.

Are there limitations to the uses of stem cells?
Yes. The range of different types of cells that stem cells can change into may be limited to a set of cells which may not be useful for certain diseases. The complexity of individual diseases will govern whether stem cell therapy is applicable. Currently, we are in the beginnings of the field and therefore are limited by our lack of knowledge about the processes involved in cell differentiation, tissue generation and organogenesis, the process whereby organs develop into fully functional units. Another possible restriction is the problem of tissue rejection when stem cells from other sources are used to treat a person who is tissue- incompatible. This is a situation where adult stem cells from the patient could have great use, since they would not be recognized as foreign by their body. However, adult stem cells seem to be limited in their range of development and in the small amounts present in the body. Continued research into the control of stem cell differentiation will extend our ability to stimulate cell differentiation in a manner useful to fighting various diseases. Also it will enable us to understand how to enhance the growth of larger quantities of adult stem cells for the same purpose. Embryonic stem cells can be isolated in greater numbers and they are less limited in the number of cell types they can generate, which makes them attractive for study, but their current use has funding and ethical constraints. So the potential application of stem cell therapy to disease treatment is broad, but not without its limits.

What does the future hold?
From what I said today, you can see that the potential for stem cell therapy is immense and much of this potential is applicable to the use of adult stem cells which makes things less complicated from the ethics point of view. However, with efforts from individual organizations and states underway to fund human embryonic stem cell research, this field will also move forward rapidly. I think in the next fifteen years amazing things will be achieved in the field, as research moves along at a quickening pace. Thus the future is bright for the field of stem cell research, its application to the treatment of a variety of diseases and the resulting enhancement to the quality of life for many.

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Useful websites:

www.medlineplus.gov -- for information on all aspects of health, medical research and the latest news on medical breakthroughs

www.pubmed.gov -- to search biomedical literature

http://stemcells.nih.gov/index.asp -- stem cell information