http://onlinelibrary.wiley.com/doi/10.1002/jnr.23064/abstract;jsessionid=35622219F6929ED9B952375B676D58C5.d03t02?userIsAuthenticated=false&deniedAccessCustomisedMessage=
Keywords:
- dopaminergic neurons;
- neuronal differentiation;
- stromal cell-derived inducing activity;
- embryonic stem cells
Abstract
Human
embryonic stem cell (hESC)-derived dopaminergic (DA) neurons hold
potential for treating Parkinson's disease (PD) through cell replacement
therapy. Generation of DA neurons from hESCs has been achieved by
coculture with the stromal cell line PA6, a source of stromal
cell-derived inducing activity (SDIA). However, the factors produced by
stromal cells that result in SDIA are largely undefined. We previously
reported that medium conditioned by PA6 cells can generate functional DA
neurons from NTera2 human embryonal carcinoma stem cells. Here we show
that PA6-conditioned medium can induce DA neuronal differentiation in
both NTera2 cells and the hESC I6 cell line. To identify the factor(s)
responsible for SDIA, we used large-scale microarray analysis of gene
expression combined with mass spectrometric analysis of PA6-conditioned
medium (CM). The candidate factors, hepatocyte growth factor (HGF),
stromal cell-derived factor-1 α (SDF1α), secreted frizzled-related
protein 1 (sFRP1), and vascular endothelial growth factor D (VEGFD) were
identified, and their concentrations in PA6 CM were established by
immunoaffinity capillary electrophoresis. Upon addition of SDF1α, sFRP1,
and VEGFD to the culture medium, we observed an increase in the number
of cells expressing tyrosine hydroxylase (a marker for DA neurons) and
βIII-tubulin (a marker for immature neurons) in both the NTera2 and I6
cell lines. These results indicate that SDF1α, sFRP1, and VEGFD are
major components of SDIA and suggest the potential use of these defined
factors to elicit DA differentiation of pluripotent human stem cells for
therapeutic intervention in PD. © 2012 Wiley Periodicals, Inc.
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