Senate Appropriations Subcommittee on Labor, Health and Human Services, Education and Related Agencies – Testimony by David A. Prentice, PhD

Date: 02/07/2000

February 7, 2000

David A. Prentice, PhD

Prof. of Life Sciences, Indiana State University; Adjunct Prof. of Molecular Genetics, Indiana University School of Medicine

What is a “stem cell”? At the most basic level, it is a cell that can proliferate with almost unlimited potential, maintaining a pool of growing and dividing cells, with the added ability that some of the daughter cells can differentiate into specific cell types. Thus, a stem cell allows replenishment of itself while providing for specific functional cell types needed by the body. If we consider the range of human life, from the single-celled human embryo through the adult, we see that stem cells can be derived at various points along this developmental continuum. Some workers have taken very early human embryos (a few days old), allowed the embryo to develop a few more days, and removed the inner cells destined to form the embryo; these cells in culture form “embryonic stem cells” (ES cells.) Because they are derived so early in development, they are said to be “totipotent”–totally potent to form any specific cell type in the body, or sometimes termed “pluripotent”–able to form many potential specific cell types. While this is a tantalizing source of stem cells, it is perhaps because of this unlimited potential and the numerous developmental signals needed to become a specific cell type that it also may be a less controllable source–a study with mouse embryonic stem cells indicates that at times these cells, when injected into mice, form tumors (teratocarcinomas). Another source of human embryonic stem cells is later human embryos, from 5-9 weeks old. The primordial germ cells from these embryos (cells destined to form the egg or sperm cells in the adult) also can form embryonic stem cells in culture. However, use of these cells for treatment of disease or organ regeneration, as well as the use of embryonic stem cells from early human embryos as proposed by NIH, faces a major hurdle immune rejection. Even early embryonic cells already have the molecules on their surface which lead to an immune response in the host, or even a response of the transplant against the host (graft-versus-host disease.) Thus, use of embryonic stem cells for tissue regeneration faces the same problem as normal organ transplants the body of the person receiving the embryonic stem cells will reject them, unless large doses of toxic immunosuppressive drugs are used. One way to avoid this problem might be to form a clone of the patient (but of course this procedure is also highly controversial!); the embryonic stem cells from this procedure would not be rejected, but of course the human embryo must still be destroyed to isolate early embryonic stem cells.

Fortunately, there is an equally exciting, non-controversial alternative the use of adult, or mature, stem cells. These more developed stem cells are also found in infants and children. Our bodies continue to grow along that developmental continuum once we are born, and there is a continual need to replenish worn out or damaged cells. In the infant and even in the adult, there remains a reservoir of stem cells in many tissues. These cells are more limited in their scope of development; termed “pluripotent” or “multipotent” stem cells, because they can replenish themselves and can contribute to formation of specific cell types in multiple tissues. A simple example would be the stem cell which makes your skin (epidermis.) These cells are at the bottom-most layer of our skin, where they divide to maintain a reservoir of epidermal stem cells, and also to provide the differentiated cells which make up our skin. Only a few years ago it was thought that our bodies contained only a very few stem cells, such as the ones for skin, the intestinal lining, or for blood cells. We now know that there are many more stem cells in our adult bodies, and that these cells can accomplish an astonishing range of tissue replenishments. And one distinct advantage of these adult stem cells is that you can use your own cells to regenerate tissue, totally circumventing the problem of immune rejection.

The variety of adult stem cells, as well as their range of replacement possibilities, is a fairly recent discovery, but the number of such existing cells and their potential continues to grow. One recent example is neural stem cells. Until recently the scientific dogma was that the brain and nerves did not replenish themselves. We now know that not only can they replenish themselves, but that these neural stem cells can “redefine” themselves, even forming blood cells! In their report the researchers found that adult neural stem cells were as effective in reconstituting the immune system as fetal neural stem cells. In another study, workers found that they could “re-seed” the damaged brains of mice with adult neural stem cells, and these stem cells could multiply and repair the brains.

Bone marrow stem cells seem to be one of the most adaptable of adult stem cells. These “stromal” (or “mesenchymal”) cells are being developed commercially to treat numerous diseases and regenerate a wide range of tissues. Hematopoietic (blood-forming) stem cells from bone marrow as well as circulating blood have been used extensively in clinical applications with good success.

Within the past 2 years, a tremendous variety of adult stem cells have been reported. One of the most exciting discoveries is the tremendous versatility of these stem cells. Bone marrow, as mentioned before, seems one of the most versatile, able to regenerate not only itself, but tissues such as bone, cartilage, tendon, muscle, fat, blood cells, and even such tissues as liver and neural cells. It has been found that it takes only one bone marrow stem cell to re-seed the entire bone marrow. Even the bloodstream contains circulating stem cells which can be specifically harvested, expanded in culture, and used to regenerate bone marrow and blood cells. Brain, a tissue previously thought not able to regenerate, contains neural stem cells which can replace not only brain and nerve, but even transform itself into blood cells. Skeletal muscle contains stem cells which can reform more skeletal muscle, and also tissues such as smooth muscle, blood, bone, cartilage, fat, and possibly heart muscle. Other stem cells which have been identified include those from skin (epidermis), the cornea, and possibly from heart, liver, and lung. The conditions have been identified to allow large-scale expansion of adult stem cells in culture, making these cells an almost unlimited source. Moreover, not only do the adult stem cells retain their potential after long-term culture, it has been shown that they retain their abilities even after frozen storage, raising the possibility of “banking” adult stem cells for future use.

Clinical trials are already underway with many of these adult stem cells. Bone marrow stem cells are being used to help patients treated for various cancers, to help regenerate bone, to form cartilage in children with bone-related growth defects, and to replace bone marrow and blood cells. Peripheral blood stem cells have already been shown in one study to be as good as or better than traditional bone marrow transplants. Blood-forming stem cells have been used to treat autoimmune diseases such as multiple sclerosis, lupus, and juvenile rheumatoid arthritis. Corneal stem cells have been used to treat patients in which traditional corneal transplants were unsuccessful. Skin for transplants is becoming commercially available one small piece of tissue about the size of your fingertip can be grown to cover the area of 6 football fields. In summary, adult stem cells have not only been shown to have a promising future for treatment of diseases, but are already bearing fruit in the realization of these promises.

Regenerative Medicine Potential Using Adult Stem Cells

Graphic: Adapted from artwork supplied by Osiris Therapeutics Ricki Lewis; AHuman Mesenchymal Stem Cells Differentiate in the Lab@; The Scientist, vol. 13, #8, p. 1; April 12, 1999. www.the-scientist.library.upenn.edu/yr1999/apr/lewis_p1_990412.html

CURRENT CLINICAL APPLICATIONS OF ADULT STEM CELLS

Lymphoma, multiple myeloma, other leukemias
Breast cancer, Neuroblastoma, renal cell carcinoma, Ovarian, & other solid tumors
Autoimmune diseases-multiple sclerosis, systemic lupus erythematosus, juvenile rheumatoid arthritis, rheumatoid arthritis
Sickle cell anemia
Corneal scarring
Osteogenesis imperfecta (treating children; condition leads to bone and cartilage deformities)

POTENTIAL and PROPOSED APPLICATIONSBSHORT-TERM

Neural stem cells–Parkinson=s, Alzheimer=s, spinal cord injury, other nervous system problems (currently shown to work in mice and rats)
Heart treatments–regenerate cardiac muscle, heart valves (currently shown to work in sheep)

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