期刊
STEM CELLS AND DEVELOPMENT
卷 22, 期 3, 页码 374-382出版社
MARY ANN LIEBERT INC
DOI: 10.1089/scd.2012.0198
关键词
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资金
- Ministry of Education, Culture, Sports, Science and Technology (MEXT) in Japan
- Grants-in-Aid for Scientific Research [24592124] Funding Source: KAKEN
Although transplanted pluripotent stem cell-derived neurons can contribute to functional recovery in animal models of Parkinson's disease, the risk of tumor formation hinders clinical applications of this approach. Removing undifferentiated cells from the donor population is critical to reduce tumorigenesis. Moreover, immature neural progenitors in transplants can proliferate unpredictably, resulting in neural overgrowth and long-term risks of compressing the surrounding host tissue. Because Notch signaling plays a role in maintaining the multipotency and proliferative capacity of neural progenitors, we used gamma-secretase inhibitors (GSIs) to dampen Notch signaling in human-induced pluripotent stem cell-derived neural progenitors before transplantation and examined the effects on the growth of proliferative grafts. We observed a marked reduction in the percentage of dividing cells and increased neuronal maturation in GSI-treated samples in vitro. Next, grafts were transplanted into the striata of nonobese diabetic/severe combined immune deficiency mice. Histological analyses performed 8 weeks after the operation showed that grafts pretreated with GSIs-N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester or compound E-were significantly smaller than control samples. Immunohistologic analyses revealed that briefly treating the donor population with GSIs not only reduced the graft volume, but also altered the composition of the graft; control grafts showed neural overgrowth with numerous PAX6(+) and Ki67(+) neural rosettes, whereas GSI-treated samples developed into mature neuronal grafts containing primarily Tub beta 3(+) cells. These results suggest that pretreating potentially proliferative progenitors with GSIs may improve the safety of cell replacement therapies using pluripotent stem cells.
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