In vitro and in vivo enhanced generation of human A9 dopamine neurons from neural stem cells by Bcl-XL.
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(L) enhances the generation of DAn from VM human neural stem cells. Mechanistically, Bcl-X(L) not only exerts the expected antiapoptotic effect but also induces proneural (NGN2 and NEUROD1) 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 (EN1, LMX1B, PITX3, NURR1, VMAT2, GIRK2, and dopamine transporter) is thus enhanced by Bcl-X(L). These effects on neurogenesis occur in parallel to a decrease in glia generation. These in vitro Bcl-X(L) effects are paralleled in vivo, after transplantation in hemiparkinsonian rats, where hVM1-Bcl-X(L) cells survive, integrate, and differentiate into DAn, alleviating behavioral motor asymmetry. Bcl-X(L) then allows for human fetal VM stem cells to stably generate mature SNpc DAn both in vitro and in vivo and is thus proposed as a helpful factor for the development of cell therapies for neurodegenerative conditions, Parkinson disease in particular.
Courtois
Elise T
ET
Center of Molecular Biology Severo Ochoa (Consejo Superior de Investigaciones Científicas-UAM), Department of Molecular Biology, Autonomous University of Madrid, 28049 Madrid, Spain.
Castillo
Claudia G
CG
Center of Molecular Biology Severo Ochoa (Consejo Superior de Investigaciones Científicas-UAM), Department of Molecular Biology, Autonomous University of Madrid, 28049 Madrid, Spain; Department of Biochemistry, Faculty of Medicine, University of San Luis Potosí, 782 San Luis Potosí, México.
Seiz
Emma G
EG
Center of Molecular Biology Severo Ochoa (Consejo Superior de Investigaciones Científicas-UAM), Department of Molecular Biology, Autonomous University of Madrid, 28049 Madrid, Spain.
Ramos
Milagros
M
Center of Molecular Biology Severo Ochoa (Consejo Superior de Investigaciones Científicas-UAM), Department of Molecular Biology, Autonomous University of Madrid, 28049 Madrid, Spain.
Bueno
Carlos
C
Institute of Neurosciences, University Miguel Hernandez of Elche, 03550 Alicante, Spain.
Liste
Isabel
I
Center of Molecular Biology Severo Ochoa (Consejo Superior de Investigaciones Científicas-UAM), Department of Molecular Biology, Autonomous University of Madrid, 28049 Madrid, Spain.
Martínez-Serrano
Alberto
A
Center of Molecular Biology Severo Ochoa (Consejo Superior de Investigaciones Científicas-UAM), Department of Molecular Biology, Autonomous University of Madrid, 28049 Madrid, Spain. Electronic address: amserrano@cbm.uam.es.
D000818:Animals; D017209:Apoptosis; D001522:Behavior, Animal; D002454:Cell Differentiation; D002460:Cell Line; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008564:Membrane Potentials; D009474:Neurons / Q000378:metabolism*; D010300:Parkinson Disease; D010641:Phenotype; D051381:Rats; D017207:Rats, Sprague-Dawley; D013234:Stem Cells / Q000166:cytology*; D013378:Substantia Nigra / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism*
D051020:bcl-X Protein; D004298:Dopamine