期刊
STEM CELL REPORTS
卷 8, 期 3, 页码 619-633出版社
CELL PRESS
DOI: 10.1016/j.stemcr.2017.01.022
关键词
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资金
- Strategic Positioning Fund for Genetic Orphan Diseases [SPF2012/005]
- Agency for Science, Technology and Research (Singapore) [1431AFG122]
- Tier 1 grant from Ministry of Education (Singapore) [R-172-000-297-112]
- Singapore Immunology Network (SIgN) core funding
- A*STAR Research Attachment Program (ARAP)
- A*STAR Singapore International Graduate Award (SINGA)
Huntington disease (HD) is a dominant neurodegenerative disorder caused by a CAG repeat expansion in HTT. Here we report correction of HD human induced pluripotent stem cells (hiPSCs) using a CRISPR-Cas9 and piggyBac transposon-based approach. We show that both HDand corrected isogenic hiPSCs can be differentiated into excitable, synaptically active forebrain neurons. We further demonstrate that phenotypic abnormalities in HD hiPSC-derived neural cells, including impaired neural rosette formation, increased susceptibility to growth factor withdrawal, and deficits in mitochondrial respiration, are rescued in isogenic controls. Importantly, using genome-wide expression analysis, we show that a number of apparent gene expression differences detected between HD and non-related healthy control lines are absent betweenHDand corrected lines, suggesting that these differences are likely related to genetic background rather than HD-specific effects. Our study demonstrates correction of HD hiPSCs and associated phenotypic abnormalities, and the importance of isogenic controls for disease modeling using hiPSCs.
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