title: 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.
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 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.
authors.affiliation: Department of Biochemistry & Molecular Biology, College of Medicine, Hanyang University, #17 Haengdang-dong, Sungdong-gu, Seoul 133-791, Republic of Korea.
authors.forename: Jae-Won
authors.initials: JW
authors.lastname: Shim
authors.forename: Chang-Hwan
authors.initials: CH
authors.lastname: Park
authors.forename: Yong-Chul
authors.initials: YC
authors.lastname: Bae
authors.forename: Jin-Young
authors.initials: JY
authors.lastname: Bae
authors.forename: Seungsoo
authors.initials: S
authors.lastname: Chung
authors.forename: Mi-Yoon
authors.initials: MY
authors.lastname: Chang
authors.forename: Hyun-Chul
authors.initials: HC
authors.lastname: Koh
authors.forename: Hyun-Seob
authors.initials: HS
authors.lastname: Lee
authors.forename: Se-Jin
authors.initials: SJ
authors.lastname: Hwang
authors.forename: Ki-Hwan
authors.initials: KH
authors.lastname: Lee
authors.forename: Yong-Sung
authors.initials: YS
authors.lastname: Lee
authors.forename: Cha-Yong
authors.initials: CY
authors.lastname: Choi
authors.forename: Sang-Hun
authors.initials: SH
authors.lastname: Lee
mesh_terms: 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
chemical_list: 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