Goals for Stem Cell Transplantation

The strategy of stem cell approaches to PD is to hormonally induce stem cell differentiation into nigrostriatal dopaminergic neurons or their precursors and then to transplant them into patients. The hope is that these transplanted cells will survive, re-innervate the striatum, and functionally replace dopaminergic cells that have been lost as a result of disease progression. These goals result in considerable challenge and complexity.

The ideal stem cell source would have the capacity for indefinite clonal expansion to allow a small number of donor sources to be utilized to treat a much larger number of patients. This expansion would have to be free of genetic mutation and would have to cease once transplantation took place. The cells would also require the capacity for controlled differentiation into phenotypically appropriate dopaminergic neurons. For example, the generated neurons should not only produce dopamine but also must have the similar capacity for regulation and other aspects of functionality as native neurons.

During production, not all stem cells would be expected to differentiate into the same progeny cells. Although some cells may form neurons, others may form glial cells. A mechanism through which to select neurons from this heterogeneous background of surrounding cells in culture would be required. Of course, proper functioning of transplanted neurons may require the presence of supporting cells, which would also need to be produced and sustained in the transplanted tissue.

The transplanted stem cells would have to cease to divide or to differentiate in an uncoordinated or uncontrolled fashion once transplantation had taken place. Otherwise, the transplant might either become a tumor, if growth continued, or lose functionality over time, if differentiation progressed. Methods to ensure that the transplanted cells are not rejected by the recipient would also have to be developed. As described earlier, immunological rejection may have been a critical factor in the failure of fetal transplantation studies.

Finally, and most importantly, transplantation of these cells would have to result in the substantial improvement or reversal of the symptoms of PD. Loss of dopaminergic neurons is associated with bradykinesia, rigidity, postural instability, and tremor. These symptoms might be expected to improve with stem cell transplantation. However, additional nondopaminergic symptoms such as dementia, autonomic dysfunction, depression, and sleep disturbance would likely remain. Furthermore, stem cell therapies should not produce disabling dopamine-associated side effects, such as troubling dyskinesia. As with any invasive or complex therapy, serious consideration will have to be given to cost relative to changes in patient quality of life. Despite these substantial challenges, several different stem cell types have been considered and studied.

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