Chapter 067. Applications of Stem Cell Biology in Clinical Medicine (Part 3)

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Diabetes Mellitus The success of islet cell and pancreas transplantation provides proof of concept for a cell-based approach for type I diabetes. However, the demand for donor pancreata far exceeds the number available, and maintenance of long-term graft survival remains a problem. The search for a renewable source of stem cells capable of regenerating pancreatic islets has therefore been intensive. Pancreatic βcell turnover occurs in the normal pancreas, although the source of the new βcells is controversial. Attempts to promote endogenous regenerative processes have not yet been successful, but this remains a potentially viable approach. A number of different cell...

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Chapter 067. Applications of Stem Cell Biology in Clinical Medicine (Part 3) Diabetes Mellitus The success of islet cell and pancreas transplantation provides proof of concept for a cell-based approach for type I diabetes. However, the demand for donor pancreata far exceeds the number available, and maintenance of long-term graft survival remains a problem. The search for a renewable source of stem cells capable of regenerating pancreatic islets has therefore been intensive. Pancreatic βcell turnover occurs in the normal pancreas, although the source of the new βcells is controversial. Attempts to promote endogenous regenerative processes have not yet been successful, but this remains a potentially viable approach. A number of different cell types are candidates for use in stem cell replacement, including ES cells, hepatic progenitor cells, pancreatic ductal progenitor cells, and bone marrow stem cells. Successful therapy will depend on
developing a source of cells that can be amplified and have the ability to synthesize, store, and release insulin when it is required, primarily in response to changes in the glucose level. The proliferative capacity of the replacement cells must be tightly regulated to avoid excessive expansion of βcell numbers with the consequent development of hyperinsulinemia/hypoglycemia, and the cells must avoid immune rejection. Although ES cells can be differentiated into cells that produce insulin, these cells have relatively low insulin content and a high rate of apoptosis, and they generally lack the capacity to normalize blood glucose in diabetic animals. Thus, ES cells have not yet been useful for the large-scale production of differentiated islet cells. During embryogenesis, the pancreas, liver, and gastrointestinal tract are all derived from the anterior endoderm, and transdifferentiation of the pancreas to liver and vice versa has been observed in certain pathologic conditions. Multipotential stem cells also reside within gastric glands and intestinal crypts. Thus, hepatic, pancreatic, and/or gastrointestinal precursor cells may be candidates for cell-based therapy of diabetes. Nervous System Neural cells have been differentiated from a variety of stem cell populations. Human ES cells can be induced to generate neural stem cells, and these cells can give rise to neurons, oligodendroglia, and astrocytes. These neural
stem cells have been transplanted into the rodent brain with formation of appropriate cell types and no tumor formation. Multipotent stem cells present in the adult brain can also generate all of the major neural cell types, but highly invasive procedures would be necessary to obtain autologous cells. Fetal neural stem cells derived from miscarriages or abortuses are an alternative, and a clinical trial of fetal neural stem cells in Batten disease is commencing. Transdifferentiation of bone marrow and adipose stem cells into neural stem cells, and vice versa, has been reported, and clinical trials of such cells have begun for a number of neurologic disorders. Clinical trials of a conditionally immortalized human cell line and of human umbilical cord blood cells in stroke are also planned. Neurologic disorders that have already been targeted for stem cell therapies include spinal cord injury, amyotrophic lateral sclerosis, stroke, traumatic brain injury, Batten disease, and Parkinson's disease. In Parkinson's disease, the major motor features result from the loss of a single cell population, dopaminergic neurons within the substantia nigra pars compacta. Two clinical trials of fetal nigral transplantation failed to meet their primary endpoint and were complicated by the development of dyskinesia. Transplantation of stem cell– derived dopamine-producing cells offers a number of potential advantages over fetal transplants, including the ability of stem cells to migrate and disperse within tissue, the potential for engineering regulatable release of dopamine, and the ability to engineer cells to produce factors that will enhance cell survival.
Nevertheless, the experience with fetal transplants points out the difficulties that may be encountered. At least some of the neurologic dysfunction after spinal cord injury reflects demyelination, and both ES cells and marrow-derived stem cells are able to facilitate remyelination after experimental spinal cord injury. Clinical trials of marrow-derived stem cells have already begun, and this may be the first disease targeted for the clinical use of ES cells. Marrow-derived stem cells are also being used in the treatment of stroke, traumatic brain injury, and amyotrophic lateral sclerosis (ALS), where possible benefits are more likely to be indirect trophic effects or remyelination rather than neuron replacement. At present, no population of transplanted stem cells has been shown to generate neurons that extend axons over long distances to form synaptic connections (such as would be necessary for replacement of upper motor neurons in ALS, stroke, or other disorders). Liver Transplantation is currently the only successful treatment for end-stage liver diseases, but this approach is limited by the shortage of liver grafts. Clinical trials of hepatocyte transplantation demonstrate that it can potentially substitute for organ transplantation, but the paucity of available cells also limits this strategy. Potential sources of stem cells include endogenous liver stem cells (such as oval cells), ES cells, bone marrow cells, and umbilical cord blood cells. Although a
series of studies in humans as well as animals suggested that transplanted bone marrow stem cells can generate hepatocytes, this phenomenon largely reflects the fusion of the transplanted cells with endogenous liver cells, giving the erroneous appearance of new hepatocytes. ES cells have been differentiated into hepatocytes and transplanted in animal models of liver failure without formation of teratomas.