Abstract
Clinical trials engrafting human fetal ventral mesencephalic tissue have demonstrated, in principle, that cell replacement therapy provides substantial long-lasting improvement of motor impairments generated by Parkinson's Disease (PD). The use of fetal tissue is not practical for widespread clinical implementation of this therapy, but stem cells are a promising alternative source for obtaining replacement cells. The ideal stem cell source has yet to be established and, in this review, we discuss the potential of neural stem cells in the adult subventricular zone (SVZ) as an autologous source of replacement cells. We identify three key challenges for further developing this potential source of replacement cells: (1) improving survival of transplanted cells, (2) suppressing glial progenitor proliferation and survival, and (3) developing methods to efficiently produce dopaminergic neurons. Subventricular neural stem cells naturally produce a dopaminergic interneuron phenotype that has an apparent lack of vulnerability to PD-mediated degeneration. We also discuss whether olfactory bulb dopaminergic neurons derived from adult SVZ neural stem cells are a suitable source for cell replacement strategies.
Highlights
Parkinson’s Disease (PD) is one of the most prevalent neurodegenerative disorders and afflicts ∼1% of the population over 60 years of age in industrialized nations (Nussbaum and Ellis, 2003)
Neural progenitor cells isolated by a Percoll gradient protocol, cultured for 2 weeks in media containing epidermal growth factor (EGF) and FGF2; cells were labeled with BrdU
subventricular zone (SVZ)/OLFACTORY BULB DOPAMINERGIC PHENOTYPE AS A POTENTIAL REPLACEMENT CELL SOURCE Adult SVZ neural stem cells normally generate dopaminergic interneurons and both Mash1 and Nurr1-family transcription factors are important for specification of these interneurons (Cave and Baker, 2009)
Summary
Parkinson’s Disease (PD) is one of the most prevalent neurodegenerative disorders and afflicts ∼1% of the population over 60 years of age in industrialized nations (Nussbaum and Ellis, 2003). Clinical trials engrafting human fetal ventral mesencephalic tissue containing dopaminergic neuronal progenitors into the striatum demonstrated, in principle, that this approach can provide substantial long-lasting improvement of motor symptoms (Widner et al, 1992; Defer et al, 1996; Freed et al, 2001; Mendez et al, 2002; Olanow et al, 2003). Some patients in these trials improved post-operatively to a point where L-DOPA therapy was no longer required, but others experienced negligible long-term improvement and, in some cases, severe graft-induced dyskinesias developed and required additional surgical intervention. Advancing induced pluripotent stem cells to a clinical setting faces many of same challenges confronting the use of embyronic stem cells, including improvement in the dopaminergic neuron yields and prevention of tumor formation in the recipient
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