Genomica

http://www.nature.com/nature/journal/v418/n6893/full/nature00900.html

Article
Nature 418, 50-56 (4 July 2002) | doi:10.1038/nature00900; Received 24 April 2002; Accepted 12 June 2002; Published online 20 June 2002
Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson's disease
Jong-Hoon Kim2, Jonathan M. Auerbach2,2, José A. Rodríguez-Gómez, IvánVelasco, Denise Gavin, Nadya Lumelsky, Sang-Hun Lee2, John Nguyen2, Rosario Sánchez-Pernaute2, Krys Bankiewicz2 & Ron McKay
Laboratory of Molecular Biology, National Institute of Neurological Disorders and Stroke, National Institute of Health, Bethesda, Maryland 20892, USA
These authors contributed equally to this work.
Present addresses: NeuralStem, Inc., 205 Perry Parkway, Gaithersburg, Maryland20877, USA (J.M.A.); Department of Biochemistry, College of Medicine, Hanyang University, 133-791 Seoul, Korea (S.-H.L.); Department of Neurosurgery, University of California, San Francisco, California 94103, USA (J.N., K.B.); Neuroregeneration Laboratory, Harvard Medical School, McLean Hospital, Belmont, Massachusetts 02478, USA (R.S.-P.).
Correspondence to: Ron McKay Correspondence andrequests for materials should be addressed to R.M. (e-mail: Email: mckay@codon.nih.gov).
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Abstract
Parkinson's disease is a widespread condition caused by the loss of midbrain neurons that synthesize the neurotransmitter dopamine. Cells derived from the fetal midbrain can modify the course of the disease, but they are an inadequate source of dopamine-synthesizing neurons because theirability to generate these neurons is unstable. In contrast, embryonic stem (ES) cells proliferate extensively and can generate dopamine neurons. If ES cells are to become the basis for cell therapies, we must develop methods of enriching for the cell of interest and demonstrate that these cells show functions that will assist in treating the disease. Here we show that a highly enriched population ofmidbrain neural stem cells can be derived from mouse ES cells. The dopamine neurons generated by these stem cells show electrophysiological and behavioural properties expected of neurons from the midbrain. Our results encourage the use of ES cells in cell-replacement therapy for Parkinson's disease.
Fetal midbrain precursors can proliferate and differentiate into dopamine-synthesizing neurons invitro, and transplantation of these cells leads to recovery in a rat model of Parkinson's disease1, 2. However, these precursor cells, which are derived from either rodent or human midbrain, generate dopamine neurons for only short periods in culture. ES cells can proliferate extensively in an undifferentiated state and may provide an unlimited source of many cell types. A related benefit ofusing ES cells is their accessibility for genetic engineering, which will permit the isolation and functional analysis of specific cell types. The isolation of human ES cells and the related embryonic germ cells has stimulated interest in their potential clinical value3, 4. Although the use of ES cells in cell therapy is widely discussed, there are few cases showing that ES cell technology can besuccessfully applied to animal models of disease5, 6, 7. We have defined signals that improve the efficiency of dopamine-neuronal differentiation from ES cells, but this approach may still provide too few neurons for widespread use8. The purpose of our study here was to develop a method of further increasing the efficiency of midbrain-specific generation of dopamine neurons from ES cells, and todemonstrate that these cells can functionally integrate into host tissue as well as lead to recovery in a rodent model of Parkinson's disease.
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Generation of midbrain CNS precursors
Previously, we developed a five-stage method that leads to the efficient differentiation of ES cells into neurons8, 9. Nuclear receptor related-1 (Nurr1) is a transcription factor that has a role in the...