In Vitro and in Vivo Enhanced Generation of Human A9 Dopamine Neurons from Neural Stem Cells by Bcl-XL*
Identifieur interne : 000252 ( Main/Curation ); précédent : 000251; suivant : 000253In Vitro and in Vivo Enhanced Generation of Human A9 Dopamine Neurons from Neural Stem Cells by Bcl-XL*
Auteurs : Elise T. Courtois ; Claudia G. Castillo ; Emma G. Seiz ; Milagros Ramos ; Carlos Bueno ; Isabel Liste ; Alberto Martínez-SerranoSource :
- The Journal of Biological Chemistry [ 0021-9258 ] ; 2010.
Abstract
Human neural stem cells derived from the ventral mesencephalon (VM) are powerful research tools and candidates for cell therapies in Parkinson disease. Previous studies with VM dopaminergic neuron (DAn) precursors indicated poor growth potential and unstable phenotypical properties. Using the model cell line hVM1 (human ventral mesencephalic neural stem cell line 1; a new human fetal VM stem cell line), we have found that Bcl-XL enhances the generation of DAn from VM human neural stem cells. Mechanistically, Bcl-XL not only exerts the expected antiapoptotic effect but also induces proneural (
Url:
DOI: 10.1074/jbc.M109.054312
PubMed: 20106970
PubMed Central: 2843236
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PMC:2843236Le document en format XML
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Enhanced Generation of Human A9 Dopamine Neurons from Neural Stem Cells by Bcl-X<sub>L</sub>
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<front><div type="abstract" xml:lang="en"><p>Human neural stem cells derived from the ventral mesencephalon (VM) are powerful research tools and candidates for cell therapies in Parkinson disease. Previous studies with VM dopaminergic neuron (DAn) precursors indicated poor growth potential and unstable phenotypical properties. Using the model cell line hVM1 (human ventral mesencephalic neural stem cell line 1; a new human fetal VM stem cell line), we have found that Bcl-X<sub>L</sub>
enhances the generation of DAn from VM human neural stem cells. Mechanistically, Bcl-X<sub>L</sub>
not only exerts the expected antiapoptotic effect but also induces proneural (<italic>NGN2</italic>
and <italic>NEUROD1</italic>
) and dopamine-related transcription factors, resulting in a high yield of DAn with the correct phenotype of substantia nigra pars compacta (SNpc). The expression of key genes directly involved in VM/SNpc dopaminergic patterning, differentiation, and maturation (<italic>EN1</italic>
, <italic>LMX1B</italic>
, <italic>PITX3</italic>
, <italic>NURR1</italic>
, <italic>VMAT2</italic>
, <italic>GIRK2</italic>
, and dopamine transporter) is thus enhanced by Bcl-X<sub>L</sub>
. These effects on neurogenesis occur in parallel to a decrease in glia generation. These <italic>in vitro</italic>
Bcl-X<sub>L</sub>
effects are paralleled in <italic>vivo</italic>
, after transplantation in hemiparkinsonian rats, where hVM1-Bcl-X<sub>L</sub>
cells survive, integrate, and differentiate into DAn, alleviating behavioral motor asymmetry. Bcl-X<sub>L</sub>
then allows for human fetal VM stem cells to stably generate mature SNpc DAn both <italic>in vitro</italic>
and <italic>in vivo</italic>
and is thus proposed as a helpful factor for the development of cell therapies for neurodegenerative conditions, Parkinson disease in particular.</p>
</div>
</front>
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