The Role of Lmx1a in the Differentiation of Human Embryonic Stem Cells into Midbrain Dopamine Neurons in Culture and After Transplantation into a Parkinson's Disease Model§

Authors

  • Jingli Cai,

    1. Farber Institute for Neurosciences, Department of Neurology, Thomas Jefferson University Medical College, Philadelphia, Pennsylvania, USA
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  • Angela Donaldson,

    1. Farber Institute for Neurosciences, Department of Neurology, Thomas Jefferson University Medical College, Philadelphia, Pennsylvania, USA
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  • Ming Yang,

    1. Farber Institute for Neurosciences, Department of Neurology, Thomas Jefferson University Medical College, Philadelphia, Pennsylvania, USA
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  • Michael S. German,

    1. University of California San Francisco, San Francisco, California, USA
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  • Grigori Enikolopov,

    1. Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA
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  • Lorraine Iacovitti

    Corresponding author
    1. Farber Institute for Neurosciences, Department of Neurology, Thomas Jefferson University Medical College, Philadelphia, Pennsylvania, USA
    • Farber Institute for Neurosciences, Thomas Jefferson University Medical College, Suite 462, Jefferson Hospital for Neuroscience, 900 Walnut Street, Philadelphia, Pennsylvania 19107, USA
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    • Telephone: 215-955-8118; Fax: 215-955-2992


  • Author contributions: J.C.: conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; A.D.: collection and/or assembly of data, data analysis and interpretation, approval of manuscript draft; M.Y.: conception and design, collection and/or assembly of data, data analysis and interpretation, approval of manuscript draft; M.S.G. and G.E.: provision of study material, approval of manuscript draft; L.I.: conception and design, financial support, collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript.

  • Disclosure of potential conflicts of interest is found at the end of this article.

  • §

    First published online in STEM CELLSEXPRESS October 2, 2008.

Abstract

Recent studies have provided important insight into the homeoprotein LIM homeobox transcription factor 1α (Lmx1a) and its role in the commitment of cells to a midbrain dopamine (mDA) fate in the developing mouse. We show here that Lmx1a also plays a pivotal role in the mDA differentiation of human embryonic stem (hES) cells. Thus, as indicated by small interfering RNA experiments, the transient early expression of Lmx1a is necessary for the coordinated expression of all other dopamine (DA)-specific phenotypic traits as hES cells move from multipotent human neural progenitor cells (hNPs) to more restricted precursor cells in vitro. Moreover, only Lmx1a-specified hNPs have the potential to differentiate into bona fide mDA neurons after transplantation into the 6-hydroxydopamine-treated rat striatum. In contrast, cortical human neuronal precursor cells (HNPCs) and mouse subventricular zone cells do not express Lmx1a or become mDA neurons even when placed in an environment that fosters their DA differentiation in vitro or in vivo. These findings suggest that Lmx1a may be critical to the development of mDA neurons from hES cells and that, along with other key early DA markers (i.e., Aldh1a1), may prove to be extremely useful for the selection of appropriately staged and suitably mDA-specified hES cells for cell replacement in Parkinson's disease. STEM CELLS2009;27:220–229

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