期刊
MOLECULAR PSYCHIATRY
卷 20, 期 3, 页码 361-368出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/mp.2014.22
关键词
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资金
- California Institute of Regenerative Medicine (CIRM) [RL1-00649-1]
- G Harold & Leila Y Mathers Foundation
- G Harold & Leila Y Mathers Foundation, the JPB Foundation
- Leona M and Harry B Helmsley Charitable Trust
- Robert and Mary Jane Engman
- Brain and Behavior Young Investigator Grant
- National Institute of Health (NIH) [R01 MH101454, R01 MH068770, P41 GM103533, R01MH100175, R01 DA023999, R01 NS014841]
- New York Stem Cell Foundation
- National Research Service Award (NRSA) fellowship [F32 AG039127]
- F Hoffman-La Roche Postdoctoral Fellowship Award [SFP2063]
- Kavli Institute for Neuroscience at Yale
- NARSAD
- CTSI-CN
- Chicago Biomedical Consortium
- Searle Funds at The Chicago Community Trust
- [R00 AA018387]
- [R01 AG046170]
- [R21 MH097156-01A1]
- [R01 CA163772]
- [U01AI111598-01]
Consistent with recent reports indicating that neurons differentiated in vitro from human-induced pluripotent stem cells (hiPSCs) are immature relative to those in the human brain, gene expression comparisons of our hiPSC-derived neurons to the Allen BrainSpan Atlas indicate that they most resemble fetal brain tissue. This finding suggests that, rather than modeling the late features of schizophrenia (SZ), hiPSC-based models may be better suited for the study of disease predisposition. We now report that a significant fraction of the gene signature of SZ hiPSC-derived neurons is conserved in SZ hiPSC neural progenitor cells (NPCs). We used two independent discovery-based approaches-microarray gene expression and stable isotope labeling by amino acids in cell culture (SILAC) quantitative proteomic mass spectrometry analyses-to identify cellular phenotypes in SZ hiPSC NPCs from four SZ patients. From our findings that SZ hiPSC NPCs show abnormal gene expression and protein levels related to cytoskeletal remodeling and oxidative stress, we predicted, and subsequently observed, aberrant migration and increased oxidative stress in SZ hiPSC NPCs. These reproducible NPC phenotypes were identified through scalable assays that can be applied to expanded cohorts of SZ patients, making them a potentially valuable tool with which to study the developmental mechanisms contributing to SZ.
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