Journal
JOURNAL OF NEUROCHEMISTRY
Volume 110, Issue 6, Pages 1908-1920Publisher
WILEY
DOI: 10.1111/j.1471-4159.2009.06281.x
Keywords
dopamine; Parkinson's disease; precursor cells; tyrosine hydroxylase; ventral mesencephalon
Categories
Funding
- Danish Parkinson Association
- Danish Medical Research Council [271-07-0582]
- Danish Centre for Stem Cell Research [2052-01-0045]
- European Science Foundation [ERAS-CT-2003-980409]
- European Union [QLK3-CT-2001 -02120-DANCE, NMP4-SL2008214706-EXCELL]
- Spanish Ministry of Science and Technology [MCYT-SAF2001-0841, SAF2004-03405, BIO2007-66807]
- ISC III [RD06/0010/0009]
- La Caixa Foundation [BM05-22]
- Foundation Ramon Areces
- EuroStemCell [LSHBCT-2003-503005]
- NeuroStemCell [HEALTH-F5-2008 222943]
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Neural stem cells constitute a promising source of cells for transplantation in Parkinson's disease, but a protocol for controlled dopaminergic differentiation is not yet available. Here we investigated the effect of the anti-apoptotic protein Bcl-x(L) and oxygen tension on dopaminergic differentiation and survival of a human ventral mesencephalic stem cell line (hVM1). hVM1 cells and a Bcl-x(L) over-expressing subline (hVMbcl-x(L)) were differentiated by sequential treatment with fibroblast growth factor-8, forskolin, sonic hedgehog, and glial cell line-derived neurotrophic factor. After 10 days at 20% oxygen, hVMbcl-x(L) cultures contained proportionally more tyrosine hydroxylase(TH)-positive cells than hVM1 control cultures. This difference was significantly potentiated from 11 +/- 0.8% to 17.2 +/- 0.2% of total cells when the oxygen tension was lowered to 3%. Immunocytochemistry and Q-PCR-analysis revealed expression of several dopaminergic markers besides of TH just as dopamine was detected in the culture medium by HPLC analysis. Although Bcl-x(L)-over-expression reduced cell death in the cultures, it did not alter the relative content of GABAergic, neurons, while the content of astroglial cells was reduced in hVMbcl-x(L) cell cultures compared with control. We conclude that Bcl-x(L) and lowered oxygen tension act in concert to enhance dopaminergic differentiation and survival of human neural stem cells.
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