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Mol Psychiatry. 2015 Mar;20(3):361-8. doi: 10.1038/mp.2014.22. Epub 2014 Apr 1.

Phenotypic differences in hiPSC NPCs derived from patients with schizophrenia.

Author information

  • 11] Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA [2] Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA [3] Salk Institute for Biological Studies, Laboratory of Genetics, La Jolla, CA, USA.
  • 2Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA, USA.
  • 3Salk Institute for Biological Studies, Laboratory of Genetics, La Jolla, CA, USA.
  • 41] Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA [2] Salk Institute for Biological Studies, Laboratory of Genetics, La Jolla, CA, USA.
  • 51] Department of Neurobiology and Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, CT, USA [2] Center for Neuroscience Research, Children's National Medical Center, Washington DC, USA.
  • 61] Departments of Chemistry, Northwestern University, Evanston, IL, USA [2] Department of Biomedical Engineering, Northwestern University, Evanston, IL, USA.
  • 7Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 8Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 9Center for Biosignatures Discovery Automation, Biodesign Institute, Arizona State University Tempe, Arizona, AZ, USA.
  • 10Department of Neurobiology and Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, CT, USA.
  • 11Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Abstract

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.

PMID:
24686136
[PubMed - in process]
PMCID:
PMC4182344
Free PMC Article
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