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Abstract & Commentary
Source: Barberi T, et al. Neural subtype specification of fertilization and nuclear transfer embryonic stem cells and application in parkinsonian mice. Nat Biotechnol. 2003;21:1200-1207.
The present study is one in which I participated. it is the first study to examine whether nuclear transfer stem cells are effective in an animal model of Parkinson’s disease (PD). So what is nuclear transfer? Nuclear transfer is a means of creating stem cells that are genetically identical to the donor. Essentially what one does is enucleate the embryonic stem (ES) cell. Then one can add back the nucleus from another animal, which is the donor. It is then possible to grow up stem cells, which are genetically identical to the donor animal. The present report shows that following nuclear transfer to mouse ES cells it is possible to develop selective neural subtypes. Under a set of coculture conditions, the nuclear transfer-derived ES cells were directed selectively into neural stem cells, astrocytes, oligodendrocytes, or neurons. By specifying particular conditions, it was possible to develop neurons that differentiated into GABA, dopamine, serotonin, or motor neurons. This is achieved by defining conditions to induce forebrain, midbrain, hindbrain, and spinal cord identity. The neuronal function of the ES cell-derived dopaminergic neurons was verified using electrophysiology, electromicroscopy, and measurement of neurotransmitter release. The ability of these nuclear transfer stem cells to reverse an animal model of PD was examined. Mice received unilateral 6-hydroxydopamine lesions of the striatum, which resulted in rotatory behavior. Following transfer of the nuclear transfer ES cells there was a gradual reversal of the rotatory behavior, which completely resolved at 10 weeks of age. These findings, therefore, show the feasibility of using nuclear transfer ES cells for the treatment of PD.
The present findings are of great scientific interest since they show the feasibility of using nuclear transfer ES cells. This potentially could be a great therapeutic advance since one could make ES cells genetically identical to the recipient. For instance, one could take a skin biopsy of a patient with PD and culture fibroblasts. One could then transfer the nucleus of the fibroblasts into the human ES cell and differentiate them into dopaminergic neuronal precursors. These could then be transplanted back into the PD patient. The major advantage of this approach is that no immunosuppression would be required. The one worry about using ES cells is that they may not be fully differentiated, and they could turn into cancer such as teratocarcinomas. In the present experiments, however, there was no evidence of carcinogenesis. The present experiment suggests the feasibility of what is known as "therapeutic cloning" for the development of ES cells that could be used effectively for the treatment of PD. — M. Flint Beal, Professor and Chairman; Department of Neurology; Cornell University Medical College New York, NY; Editor, Neurology Alert.