Submitted on May 8, 2006
Accepted on January 10, 2007
Tissue-Specific Stem Cells
|
Generation of Functional Dopamine Neurons from Neural Precursor Cells Isolated from the Subventricular Zone and White Matter of the Adult Rat Brain using Nurr1 Overexpression
Jae-Won Shim 1,
Chang-Hwan Park 2,
Yong-Chul Bae 3,
Jin-Young Bae 3,
Seungsoo Chung 4,
Mi-Yoon Chang 5,
Hyun-Chul Koh 6,
Hyun-Seob Lee 5,
Se-Jin Hwang 7,
Ki-Hwan Lee 5,
Yong-Sung Lee 5,
Cha-Yong Choi 8,
Sang-Hun Lee 5*
1 Department of Biochemistry & Molecular Biology, College of Medicine, Hanyang University, Seoul, Korea; School of Chemical and Biological Engineering, College of Engineering, Seoul National University, Seoul, Korea
2 Department of Microbiology, College of Medicine, Hanyang University, Seoul, Korea
3 Department of Oral Anatomy and Neurobiology, School of Dentistry, Kyungpook National University, Daegu, Korea
4 Department of Physiology, College of Medicine, Yonsei University, Seoul, Korea
5 Department of Biochemistry & Molecular Biology, College of Medicine, Hanyang University, Seoul, Korea; Institute of Mental Health, Hanyang University, Seoul, Korea
6 Department of Pharmacology, College of Medicine, Hanyang University, Seoul, Korea
7 Department of Anatomy & Cell Biology, College of Medicine, Hanyang University, Seoul, Korea
8 School of Chemical and Biological Engineering, College of Engineering, Seoul National University, Seoul, Korea
* To whom correspondence should be addressed. E-mail: leesh{at}hanyang.ac.kr.
 |
Abstract |
|---|
Neural precursor (NP) cells from adult mammalian brains can be isolated, expanded in vitro, and potentially used as cell replacement source material for treatment of intractable brain disorders. Reduced ethical concerns, lack of teratoma formation, and possible ex vivo autologous transplantation are critical advantages to using adult NP donor cells over cells from fetal brain tissue or embryonic stem cells. However, the usage of adult NP cells is limited by the ability to induce specific neurochemical phenotypes in these cells. Here, we demonstrate induction of a dopaminergic phenotype in NP cells isolated from the subventricular zone (SVZ) and white matter (WM) of rodent adult brains using overexpression of the nuclear receptor Nurr1 in vitro. Forced expression of Nurr1, a transcriptional factor specific to midbrain dopamine (DA) neuron development, caused in the adult cells an acquisition of the DA neurotransmitter phenotype and sufficient differentiation towards morphologically, phenotypically, and untra-structually mature DA neurons. Co-expression of neurogenic factor Mash1 and treatment with neurogenic cytokines BDNF and NT3 greatly enhanced Nurr1-induced DA neuron yield. The Nurr1-induced DA neurons demonstrated in vitro presynaptic DA neuronal functionality, releasing DA neurotransmitter in response to depolarization stimuli and specific DA reuptake. Furthermore, Nurr1-engineered adult SVZ NP cells survived, integrated, and differentiated into DA neurons in vivo that can reverse the behavioral deficit in the host striatum of Parkinsonian rats. These findings open the possibility for the use of precursor cells from adult brains as a cell source for neuronal replacement treatment of Parkinson's disease.
