30]][“Molecule R”

The poor response in one study could be explained by markedly fewer surviving grafted dopaminergic neurons as compared with that in openlabel trials. In the other study, patients were more severely disabled at the time of transplantation, indicating extensive degenerative changes.No or shortterm immunosuppression was given in these studies, which may be necessary to avoid immune reactions causing dysfunctional grafts.DYSKINESIAS can develop after transplantation, and become troublesome in of grafted patients. This adverse effect is not due to dopaminergic overgrowth. It may be caused by uneven and patchy reinnervation, giving rise to low or intermediate amounts of striatal dopamine, or by chronic inflammatory and immune responses around the graft.However, chromosomal aberrations have been observed in midterm cultured human ESC lines.Notably, genomic stability was found in human NSC and precursor lines from fetal forebrain and spinal cord, even after years in culture. Only of cells in fetal mesencephalic grafts are dopaminergic neurons.It is not yet known whether it is favorable to implant a pure population of dopaminergic neurons or whether the graft should also contain a specific composition of other neuron types and glial cells to induce maximum symptomatic relief.Neural fate can also be induced directly in adherent cultures.Embryoid bodies are treated with epidermal growth factor and fibroblast growth factor, or cultured with stromal cells to generate adherent neuroblasts or floating NSC aggregates.Similar treatment of adherent cultures generates neuroectodermal cells.Neuronal differentiation is induced by removal of mitogens.In vitro patterning with extracellular signals, or genetic modification, induces specific neuronal phenotypes.Stem cells can be isolated from other organs, expanded and differentiated into neural cells using, for example, FGF, retinoic acid or nerve growth factor.Stem cell technology has the potential to generate large numbers of dopaminergic neurons in standardized preparations.On the basis of results with fetal transplants in animals and humans, it is possible to identify a set of requirements that probably also need to be fulfilled by stem cellderived cells to induce marked clinical improvement: the cells should release dopamine in a regulated manner and should show the molecular, morphological and electrophysiological properties of substantia nigra neurons; the cells must be able to reverse in animals those motor deficits that resemble the symptoms in persons with PD; the yield of cells should allow for at least, grafted dopaminergic neurons to survive over the long term in each human putamen; the grafted dopaminergic neurons should reestablish a dense terminal network throughout the striatum; the grafts must become functionally integrated into host neural circuitries.Neuronswith dopaminergic phenotype surv iv ing transplantation have been generated in culture from mouse and monkey embryonic stem cells. Neural stem cells from fetal brain.Regionally specified rat and human mesencephalic precursors have been grown as neurospheres. Committed rat and human mesencephalic dopaminergic neuron precursors have been expanded.The protocols for generation of dopaminergic neurons give rise to mixed cell populations.FLUORESCENCEACTIVATED CELL SORTING of mesencephalic dopaminergic precursors has had limited success because of difficulties in finding specific surface antigens.The rate of neurogenesis doubled after a lesion of the dopamine reasch Panthenol system.In contrast, other investigators observed only aglial response and failed to detect any neurogenesis follow ing dopaminergic lesions, Y.

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