Stem Cells
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First published online August 25, 2005
Stem Cells Vol. 24 No. 3 March 2006, pp. 557 -567
doi:10.1634/stemcells.2005-0233; www.StemCells.com
© 2006 AlphaMed Press

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EMBRYONIC STEM CELLS

Stromal Cell–Derived Inducing Activity, Nurr1, and Signaling Molecules Synergistically Induce Dopaminergic Neurons from Mouse Embryonic Stem Cells

Dong-Wook Kima,b,c, Sangmi Chunga,b, Mikyeong Hwanga,b, Andrew Ferreea,d, Hsing-Chen Tsaia,b, Jae-Joon Parka,b,c, Seungsoo Chungc, Taick Sang Namc, Un Jung Kange, Ole Isacsona,d, Kwang-Soo Kima,b

a Udall Parkinson’s Disease Research Center of Excellence;
b Molecular Neurobiology Laboratories; McLean Hospital/Harvard Medical School, Belmont, Massachusetts, USA;
c Department of Physiology, Yonsei University College of Medicine, Seoul, Korea;
d Neuroregeneration Laboratories; McLean Hospital/Harvard Medical School, Belmont, Massachusetts, USA;
e Departments of Neurology and Pharmacology, Physiology, and Neurobiology, The University of Chicago, Chicago, Illinois, USA

Key Words. Embryonic stem cells • Stromal cell-derived inducing activity • Nurr1 • Dopaminergic neurons Parkinson’s disease

Correspondence: Kwang-Soo Kim, Ph.D., MRC 216, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, Massachusetts 02178, USA. Telephone: 617-855-2024; Fax: 617-855-3479; e-mail: kskim{at}mclean.harvard.edu

Received March 11, 2005; accepted for publication July 15, 2005.

To induce differentiation of embryonic stem cells (ESCs) into specialized cell types for therapeutic purposes, it may be desirable to combine genetic manipulation and appropriate differentiation signals. We studied the induction of dopaminergic (DA) neurons from mouse ESCs by overexpressing the transcription factor Nurr1 and coculturing with PA6 stromal cells. Nurr1-expressing ESCs (N2 and N5) differentiated into a higher number of neurons (~twofold) than the naïve ESCs (D3). In addition, N2/N5-derived cells contained a significantly higher proportion (>50%) of tyrosine hydroxylase (TH)+ neurons than D3 (<30%) and an even greater proportion of TH+ neurons (~90%) when treated with the signaling molecules sonic hedgehog, fibroblast growth factor 8, and ascorbic acid. N2/N5-derived cells express much higher levels of DA markers (e.g., TH, dopamine transporter, aromatic amino acid decarboxylase, and G protein–regulated inwardly rectifying K+ channel 2) and produce and release a higher level of dopamine, compared with D3-derived cells. Furthermore, the majority of generated neurons exhibited electrophysiological properties characteristic of midbrain DA neurons. Finally, transplantation experiments showed efficient in vivo integration/generation of TH+ neurons after implantation into mouse striatum. Taken together, our results show that the combination of genetic manipulation(s) and in vitro cell differentiation conditions offers a reliable and effective induction of DA neurons from ESCs and may pave the way for future cell transplantation therapy in Parkinson’s disease.




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