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

 Dong-Wook Kim  ;  Sangmi Chung  ;  Mikyeong Hwang  ;  Andrew Ferree  ;  Hsing-Chen Tsai  ;  Jae-Joon Park  ;  Seungsoo Chung  ;  Taick Sang Nam  ;  Un Jung Kang  ;  Ole Isacson  ;  Kwang-Soo Kim 
 STEM CELLS, Vol.24(3) : 557-567, 2006 
Journal Title
Issue Date
Animals ; Cell Differentiation/physiology* ; Cell Line ; Coculture Techniques ; DNA-Binding Proteins/biosynthesis* ; Dopamine/metabolism ; Embryo, Mammalian/cytology ; Embryo, Mammalian/physiology* ; Gene Expression Regulation/physiology ; Mice ; Neurons/cytology ; Neurons/physiology* ; Nuclear Receptor Subfamily 4, Group A, Member 2 ; Parkinson Disease/therapy ; Signal Transduction/physiology* ; Stem Cell Transplantation ; Stem Cells/cytology ; Stem Cells/physiology* ; Stromal Cells/cytology ; Stromal Cells/physiology ; Transcription Factors/biosynthesis*
Embryonic stem cells ; Stromal cell‐derived inducing activity ; Nurr1 ; Dopaminergic neurons Parkinson's disease
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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1. College of Medicine (의과대학) > Dept. of Physiology (생리학교실) > 1. Journal Papers
Yonsei Authors
Kim, Dong Wook(김동욱) ORCID logo https://orcid.org/0000-0002-5025-1532
Nam, Taick Sang(남택상)
Chung, Seung Soo(정승수) ORCID logo https://orcid.org/0000-0002-3119-9628
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