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Encyclopedia of Genetics, Rev. Ed. Stem Cells Field of Study: Cellular biology; Human genetics and social issues Significance: Stem cells, which can be manipulated to create unlimited amounts of specialized tissue, may be used to treat a variety of diseases and injuries that have destroyed a patient's cells, tissues, or organs. Stem cells could also be used to gain a better understanding of how genetics works in the early stages of cell development and may play a role the testing and development of drugs. Key Terms ADULT STEM CELL: an undifferentiated cell found among differentiated cells in a tissue or organ of an adult organism BLASTOCYST: a preimplantation embryo consisting of a hollow ball of two layers of cells CELL DIFFERENTIATION: the process whereby a precursor cell produces progeny that are capable of expressing a different set of genes EMBRYONIC STEM CELL: an undifferentiaed cell derived from the inner cell mass of a blastocyst MULTIPOTENCY: the ability of cells to form progeny that can differentiate into one of the different types of cells that form the living organism PLURIPOTENCY: the ability of a cell to give rise to all the differentiated cell types in an embryo TOTIPOTENCY: the ability of a single cell to express the full genome in the cells to which it gives rise by cell division Types of Stem Cells Stem cells are defined by their ability to renew themselves, their lack of differentiation, and their ability to diversify into other cell types. There are three major classes of stem cells: totipotent, pluripotent, and multipotent. Totipotent cells can differentiate to become all of the cells that make up an embryo, all of the extraembryonic tissues, and all of the postembryonic tissues and organs. Pluripotent cells have the potential to become almost all of the tissues found in an embryo but are not capable of giving rise to supporting cells and tissues. Multipotent cells are specialized stem cells capable of giving rise to one class of cells. A fertilized egg, or zygote, is totipotent. The zygote first divides into two cells about one day after fertilization and becomes an embryo. The embryonic cells remain totipotent for about four days after fertilization. At that point, the embryo consists of about eight cells. As the cells of the embryo continue to divide, they form a hollow sphere. The approximately fifty to one hundred cells on the inner side of the sphere are pluripotent and will continue developing to form the embryo, while the cells on the outer surface will give rise to the extraembryonic tissues, such as the placenta and the umbilical cord. Multipotent stem cells are found in a variety of tissues in adult mammals and are sometimes referred to as adult stem cells. They are specialized stem cells that are committed to giving rise to cells that have a particular function. Identities of some multipotent stem cells have been confirmed. Hematopoietic stem cells give rise to all the types of blood cells. Mesenchymal stem cells in the bone marrow give rise to a variety of cell types: bone cells, cartilage cells, fat cells, and other kinds of connective tissue cells such as those in tendons. Neural stem cells in the brain give rise to its three major cell types: nerve cells (neurons) and two categories of nonneuronal cells, astrocytes and oligodendrocytes. Skin stem cells occur in the basal layer of the epidermis and at the base of hair follicles. The epidermal stem cells give rise to keratinocytes, which migrate to the surface of the skin and form a protective layer. The follicular stem cells can give rise to both the hair follicle and the epidermis. Stem cells in adult mammalian tissues are rare and difficult to isolate. There is considerable debate concerning the plasticity of stem cells in adults. Plasticity is the ability of multipotent cells to exhibit pluripotency, such as the capacity of hematopoietic stem cells to differentiate into neurons. Behavior in Cell Culture During the 1980's researchers first established in vitro culture conditions that allowed embryonic stem cells to divide without differentiating. Embryonic stem cells are relatively easy to grow in culture but appear to be genetically unstable; mice cloned from embryonic stem cells by nuclear transfer suffered many genetic defects as a result of the genetic instability of the embryonic stem cells. As embryonic stem cells divide in culture, they lose the tags that tell an imprinted gene to be either turned on or turned off during development. Researchers have found that even clones made from sister stem cells show differences in their gene expression. However, these genetic changes, while having defined roles in fetal development, may have little significance in therapeutic uses, because the genes involved do not serve a critical role in adult differentiated cells. Unlike embryonic stem cells, adult stem cells do not divide prolifically in culture. When these stem cells do divide in culture, their division is unlike that of most cells. Generally, when a cell divides in culture, the two daughter cells produced are identical in appearance as well as in patterns of gene expression. However, when stem cells divide in culture, at least one of the daughter cells retains its stem cell culture while the other daughter cell is frequently a transit cell destined to produce a terminally differentiated lineage. The genes expressed in a stem cell and a transit cell are significantly different. Therefore a culture of adult stem cells may become heterogeneous in a short time. Potential Therapeutic Issues Although stem cells have significant use as models for early embryonic development, another major research thrust has been for therapeutic uses. Stem cell therapy has been limited almost exclusively to multipotent stem cells obtained from umbilical cord blood, bone marrow, or peripheral blood. These stem cells are most commonly used to assist in hematopoietic (blood) and immune system recovery following high-dose chemotherapy or radiation therapy for malignant and nonmalignant diseases such as leukemia and certain immune and genetic disorders. For stem cell transplants to succeed, the donated stem cells must repopulate or engraft the recipient's bone marrow, where they will provide a new source of essential blood and immune system cells. In addition to the uses of stem cells in cancer treatment, the isolation and characterization of stem cells and in-depth study of their molecular and cellular biology may help scientists understand why cancer cells, which have certain properties of stem cells, survive despite very aggressive treatments. Once the cancer cell's ability to renew itself is understood, scientists can develop strategies for circumventing this property. Research efforts are under way to improve and expand the use of stem cells in treating and potentially curing human diseases. Possible therapeutic uses of stem cells include treatment of autoimmune diseases such as muscular dystrophy, multiple sclerosis, and rheumatoid arthritis; repair of tissues damaged during stroke, spinal cord injury, or myocardial infarction; treatment of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS, commonly called Lou Gehrig's disease) and numerous neurological conditions such as Parkinson's, Huntington's, and Alzheimer's diseases; and replacement of insulin-secreting cells for in diabetics. Stem cells may also find use in the field of gene therapy, where a gene that provides a missing or necessary protein is introduced into an organ for a therapeutic effect. One of the most difficult problems in gene therapy studies has been the loss of expression (or insufficient expression) following introduction of the gene into more differentiated cells. Introduction of the gene into stem cells to achieve sufficient long-term expression would be a major advance. In addition, the stem cell is clearly a more versatile target cell for gene therapy, since it can be manipulated to become theoretically any tissue. A single gene transfer into a pluripotent stem cell could enable scientists to generate stem cells for blood, skin, liver, or even brain targets. Ethical Issues Concerning Use Stem cell research, particularly embryonic stem cell research, has unleashed a storm of controversy. One primary controversy surrounding the use of embryonic stem cells is based on the belief by opponents that a fertilized egg is fundamentally a human being with rights and interests that need to be protected. Those who oppose stem cell research do not want fetuses and fertilized eggs used for research purposes. Others accept the special status of an embryo as a potential human being yet argue that the respect due to the embryo increases as it develops and that this respect, in the early stages in particular, may properly be weighed against the potential benefits arising from the proposed research. Another ethical issue concerns the method by which embryonic stem cells are obtained. Embryonic stem cells are isolated from two sources: surplus embryos produced by in vitro fertilization and embryos produced by somatic cell nuclear transfer (SCNT), often referred to as therapeutic cloning. In SCNT, genetic material from a cell in an adult's body is fused with an enucleated egg cell. With the right conditions, this new cell can then develop into an embryo from which stem cells could be harvested. Opponents argue that therapeutic cloning is the first step on the slippery slope to reproductive cloning, the use of SCNT to create a new adult organism. Proponents maintain that producing stem cells by SCNT using genetic material from the patient will eliminate the possibility of rejection when the resulting stem cells are returned to the patient. Legal Status On August 9, 2001, President George W. Bush announced that federal funds could be used to support research using the sixty human embryonic stem cell lines that had been derived before that date. However, there were no restrictions placed on the types of research that could be conducted on mouse embryonic stem cell lines and no federal law or policy prohibiting the private sector from isolating stem cells from human embryos. Several states have introduced legislation to encourage research on stem cells taken from human embryos. As of March, 2003, neither reproductive cloning nor therapeutic cloning was forbidden by law in the United States. Congress was debating competing legislation; one bill proposed to ban both types of cloning, while an alternative proposal would ban only reproductive cloning. A number of states already have laws that ban human cloning for reproductive purposes, while a small number of states forbid cloning of embryos for stem cells as well. Lisa M. Sardinia See AlsoAging; Alzheimer's Disease; Autoimmune Disorders; Biochemical Mutations; Bioethics; Cancer; Cell Culture: Animal Cells; Cell Culture: Plant Cells; Cell Cycle, The; Cell Division; Cloning; Cloning: Ethical Issues; Cloning Vectors; Cystic Fibrosis; Developmental Genetics; Eugenics; Eugenics: Nazi Germany; Gene Therapy; Gene Therapy: Ethical and Economic Issues; Genetic Engineering: Medical Applications; Huntington's Disease; In Vitro Fertilization and Embryo Transfer; Infertility; Knockout Genetics and Knockout Mice; Model Organism: Mus musculus; Organ Transplants and HLA Genes; Totipotency; Transgenic Organisms. Further Reading Holland, Suzanne, Karen Lebacqz, and Laurie Zoloth, eds. The Human Embryonic Stem Cell Debate: Science, Ethics, and Public Policy (Basic Bioethics). Cambridge, Mass.: MIT Press, 2001. A collection of twenty essays organized into four sections: basic science and history of stem cell research, ethics, religious perspectives, and public policy. Kaji, Eugene H., and Jeffrey M. Leiden. "Gene and Stem Cell Therapies." Journal of the American Medical Association 285, no. 5 (2001): 545-550. An overview of stem cells from a clinical viewpoint. Includes discussion of the feasibility of stem cell therapy, future research, and ethical issues. Kiessling, Ann, and Scott C. Anderson. Human Embryonic Stem Cells: An Introduction to the Science and Therapeutic Potential. Boston: Jones and Bartlett, 2003. In the context of the social debate and public policy of the George W. Bush administration, addresses the various stem cell research from the perspectives of many disciplines, from cell biology, embryology, and endocrinolgy to transplantation medicine. Marshak, Daniel R., Richard L. Gardner, and David Gottlieb, eds. Stem Cell Biology. Woodbury, N.Y.: Cold Spring Harbor Laboratory Press, 2002. Contains papers on early embryonic development, cell cycle controls, embryonal carcinoma cells as embryonic stem cells, stem cells of human adult bone marrow, intestinal epithelial stem cells, and much more, designed for researchers new to the field of stem cell biology. Rao, Mahendra S., ed. Stem Cells and CNS Development. Totowa, N.J.: Humana Press, 2001. Collection of papers on neural stem cells, including multipotent cells in both embryos and adults, transplant therapy, drug and gene discovery, and much more. Designed for scientists. Web Site of Interest National Institutes of Health, Stem Cell Information. http://stemcells.nih.gov. Government site covering stem cell basics, the science of stem cell research, and links to related resources. |
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