期刊
CELL TRANSPLANTATION
卷 13, 期 5, 页码 535-547出版社
SAGE PUBLICATIONS INC
DOI: 10.3727/000000004783983729
关键词
neural stem cells; progenitor cells; dopamine; differentiation; tyrosine hydroxylase; transplantation; Parkinson's disease; 6-hydroxydopmine lesion
资金
- NINDS NIH HHS [R01 NS024204, R01 NS032519-14, R01 NS032519-13, NS24204, NS 43309, R01 NS032519, R01 NS024204-14, R01 NS024204-13, R01 NS043309, R01 NS024204-12S1, NS32519] Funding Source: Medline
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS043309, R01NS024204, R01NS032519, R55NS032519] Funding Source: NIH RePORTER
The development of cell replacement therapies for the treatment of neurodegenerative disorders such as Parkinson's disease (PD) may depend upon the successful differentiation of human neural stem/progenitor cells into dopamine (DA) neurons. We show here that primary human neural progenitors (HNPs) can be expanded and maintained in culture both as neurospheres (NSPs) and attached monolayers where they develop into neurons and glia. When transplanted into the 6-hydroxydopantine-lesioned rat striatum, undifferentiated NSPs survive longer (60% graft survival at 8-16 weeks vs. 30% graft survival at 8-13 weeks) and migrate farther than their attached counterparts. While both NSP and attached cells continue to express neuronal traits after transplantation, the spontaneous expression of differentiated transmitter-related traits is not observed in either cell type. However, following predifferentiation in culture using a previously described cocktail of reagents, approximately 25% of HNPs can permanently express the DA enzyme tyrosine hydroxylase (TH), even following replating and removal of the DA differentiation cocktail. When these predifferentiated HNPs are transplanted into the brain, however, TH staining is not observed, either because expression is lost or TH-expressing cells preferentially die. Consistent with the latter view is a decrease in total cell survival and migration, and an enhanced glial response in these grafts. In contrast, we found that the overall survival of HNPs is improved when cells engraft near blood vessels or CSF compartments or when they are placed into an intact unlesioned brain, suggesting that there are factors, as yet unidentified, that can better support the development of engrafted HNPs.
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