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| Description: Adult stem cells offer hope for cell therapy to treat diseases in the future because ethical issues do not impede their use. In addition, if the patient's own cells are used, immunological compatibility is not an issue. However, ES cells have been found to be superior for both differentiation potential and ability to divide in culture. Two concepts are useful to describe characteristics of adult stem cells: Plasticity is a newly recognized ability of stem cells to expand their potential beyond the tissue from which they are derived. For example, Dental pulp stem cells develop into tissue of the teeth but can also develop into neural tissue.20 Transdifferentiatio n is the direct conversion of one cell type to another,21 e.g. transdifferentiatio n of pancreatic cells into hepatic cells and vice versa has been reported in both animals and humans as has the transdifferentiatio n of blood cells into brain cells and vice versa.22 Cell fusion: ES cells can fuse in vitro with neuronal cells and with hematopoietic stem cells.17 This has started a new debate in adult stem cell plasticity, namely that some cells may have fused and the nucleus was reprogrammed instead of transdifferentiatin g. Cord blood stem cells Cord blood, from the umbilical cord, was believed to be an alternate source of hematopoietic stem cells; however, it is impossible to obtain sufficient numbers of stem cells from most cord blood collections to engraft an adult of average weight. Development continues on techniques to increase the number of these cells ex vivo. Cord blood contains both hematopoietic and non-hematopoietic stem cells.23 B. Research and Clinical Applications of Cultured Stem Cells What are the uses of Cultured Stem cells? The most prominent is cell therapy for treating conditions such as spinal cord injuries and for curing disease. Stem cells are used to investigate questions to further basic and clinical research. Here are the major applications to date: Functional Genomic studies In 1986, Gossler et al. reported using mouse ES cells to produce transgenic animals.24 Soon after, two landmark papers in the field of mouse genetics demonstrated the ability to manipulate a specific gene of ES cells.25 Combining these techniques, a specific gene can be introduced into ES cells to produce transgenic mice. This gene can be transmitted to their offspring through the germline. Today these techniques enable the study of the function of mammalian genes and proteins in the mouse (through introducing human histocompatibility genes into mice).26 Study of biological processes Studies of biological processes, namely development of the organism and progress of cancer, are facilitated by the ability to trace stem cell fate. The spleen colony assay developed by Till and McCulloch is an example study of the development of blood cells. In this method single cells were injected into heavily irradiated mice so that all the hematopoietic cells in these mice originated from the original colony. Studies of this nature helped decipher the clonal origin of cancer, Drug discovery and development The combination of isolation and purification of mouse ES cells and genetic engineering techniques has led to the use of murine ES cells in drug discovery. With the sequencing of the human genome many potential targets of new drugs have been identified. Studies using human ES may follow those of murine ES cells.27 Interest in using stem cells as models for toxicology has also grown recently.28 Cell-based therapy Cultured ES cells spontaneously form embryoid bodies containing different cell types from all three germ layers. The desired cells are isolated and cultured and the differentiated cells are then used for therapy. ES cells have been induced to differentiate into neurons, cardiomyocytes and endoderm cells. The identification of hematopoietic stem cells in mice by Till and McCulloch in 1961 heralded the use of stem cell therapy.29 By 1999, 50 diseases had been treated by bone marrow and stem cell therapy with varying degrees of success,30 among them leukemia, breast cancer, inflammatory bowel disease and osteogenesis imperfecta (a bone disease) in humans. ES and adult stem cells now offer hope for reversing the symptoms of many diseases and conditions including cancer, neurodegenerative diseases, spinal cord injuries, and heart disease. The following stem cell characteristics make them good candidates for cell-based therapies:31 i. Potential to be harvested from patients ii. High capacity of cell proliferation in culture to obtain large number of cells from a limited source iii. Ease of manipulation to replace existing non functional genes via gene transfer methods iv. Ability to migrate to host's target tissues, e.g. the brain v. Ability to integrate into host tissue and interact with surrounding tissue Following is a summary of three diseases in which stem cell-based therapy has been used. a) Heart disease Cardiovascular disease is a leading cause of death worldwide killing 17 million people each year,32 especially due to heart attack and stroke. In the United States, heart disease is the number one cause of death. The high rate of mortality associated with heart diseases is the inability to repair damaged tissue33 due to the full differentiation of heart tissue. Interruption of blood supply to the tissue causes infarction of the myocardium and death of myocardiocytes. A recent report used a swine model of atrioventricular block and transplanted human ES cell-derived cardiomyocytes into the pig's heart to work as a pacemaker.34 The ES cells survived, functioned and integrated well with the host cells. The researchers used embryoid bodies to select spontaneously beating areas of culture (cultured myocytes will actually beat in synchrony just like a heartbeat). This study bodes well for future myocardial regeneration using human ES cells. Adult stem cells have also been used in cell therapy for the heart.35 Skeletal muscle myoblast transfers showed contraction but did not differentiate into cardiomyocytes and did not integrate with the host myocardium. Ideally, both contraction and integration with host myocardium should have occurred in order for the therapy to be effective. Endothelial progenitor cells transplants halted the degenerative process but did not initiate regeneration. Early clinical studies may soon follow. Another approach is cardiac tissue engineering.36 Cohen and Leor grew embryonal heart cells in vitro with an alginate scaffold (alginate is an algal polysaccharide) to provide 3D-support and organization for the cells. They transplanted the cells with the scaffold into the scar tissue of the rats with myocardial infarction and observed extensively. The vascularization shows that there was acceptance of the engineered tissue. This unique method of treating heart disease is promising and may be explored in other animal models in the future. b) Diabetes Elevated glucose levels in the blood are responsible for diabetes. Diabetes affects 16 million Americans (5.9 percent of the population) and is the seventh leading cause of death.37 Worldwide it afflicts 120 million people and the World Health Organization estimates that the number will reach 300 million by 2025.38 Type I diabetes, or juvenile onset diabetes, is an autoimmune disease that causes destruction of the insulin-producing beta cells in the pancreas. Insulin injections are given to diabetics but they cause surges in blood glucose levels followed by a drop in the glucose levels and lack fine tuning. Pancreas transplantation has been performed in diabetics as more recently has pancreatic islet cell transplantation. The latter has the advantages that it does not require whole organ transplantation. However, the need for immunosuppression to prevent rejection of allogeneic islet transplants and a serious shortage of organ donors are lingering problems.25 The Edmonton protocol, developed by Shapiro and colleagues, is promising. This procedure transplants a large amount of islet cells and uses a glucocorticoid-free type of immunosuppression regimen. In early clinical testing it reversed diabetes in all of the patients tested. c) Stem cell therapy for diabetes Cells need to be able to self-regenerate and differentiate. Also it has been observed that the presence of all the islet cell types is preferable to only beta cells since the former are better able to respond to changing levels of glucose in the blood. Growth must be balanced with ability to produce insulin. The insulin producing cells tend not to divide and those which divide actively do not produce insulin. Adult stem cells from the pancreas have been elusive so far. However, a recent report of a clone from mouse pancreas that can generate both pancreatic and neural cell lines is exciting, as is a second report that adult small hepatocytes (liver cells) can be induced to produce insulin.39 Both reports offer hope for using adult stem cells as a treatment and cure for diabetes. d) Parkinson's Disease Parkinson's disease is the second most common neurodegenerative disease following Alzheimer's. Approximately 1.5 million people in the United States suffer from Parkinson's disease,40 which is caused when 80% or more of dopamine producing-neurons in the substantia nigra of the brain die. Normally, dopamine is secreted from the substantia nigra and transmitted to another part of the midbrain. This allows body movements to be smooth and coordinated. 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