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.
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 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 toward morphologically, phenotypically, and ultrastructurally mature DA neurons. Co-expression of neurogenic factor Mash1 and treatment with neurogenic cytokines brain-derived neurotrophic factor and neurotrophin-3 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 disease. Disclosure of potential conflicts of interest is found at the end of this article.
Shim
Jae-Won
JW
Department of Biochemistry & Molecular Biology, College of Medicine, Hanyang University, #17 Haengdang-dong, Sungdong-gu, Seoul 133-791, Republic of Korea.
Park
Chang-Hwan
CH
Bae
Yong-Chul
YC
Bae
Jin-Young
JY
Chung
Seungsoo
S
Chang
Mi-Yoon
MY
Koh
Hyun-Chul
HC
Lee
Hyun-Seob
HS
Hwang
Se-Jin
SJ
Lee
Ki-Hwan
KH
Lee
Yong-Sung
YS
Choi
Cha-Yong
CY
Lee
Sang-Hun
SH
D000818:Animals; D002454:Cell Differentiation; D002469:Cell Separation; D002470:Cell Survival; D002552:Cerebral Ventricles / Q000166:cytology*; D004268:DNA-Binding Proteins / Q000235:genetics*; D004298:Dopamine / Q000378:metabolism*; D015870:Gene Expression; D008297:Male; D009474:Neurons / Q000166:cytology* / Q000637:transplantation / Q000648:ultrastructure; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D010641:Phenotype; D051381:Rats; D017207:Rats, Sprague-Dawley; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology*; D013569:Synapses / Q000648:ultrastructure; D014157:Transcription Factors / Q000235:genetics*; D014161:Transduction, Genetic; D019076:Transgenes; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D004268:DNA-Binding Proteins; C539884:Nr4a2 protein, rat; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D014157:Transcription Factors; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine