title: Phenotypic differences in hiPSC NPCs derived from patients with schizophrenia.
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.
authors.affiliation: 1] 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.
authors.forename: K
authors.initials: K
authors.lastname: Brennand
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: J N
authors.initials: JN
authors.lastname: Savas
authors.affiliation: Salk Institute for Biological Studies, Laboratory of Genetics, La Jolla, CA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Kim
authors.affiliation: 1] 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.
authors.forename: N
authors.initials: N
authors.lastname: Tran
authors.affiliation: Salk Institute for Biological Studies, Laboratory of Genetics, La Jolla, CA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Simone
authors.affiliation: 1] 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.
authors.forename: K
authors.initials: K
authors.lastname: Hashimoto-Torii
authors.affiliation: 1] Departments of Chemistry, Northwestern University, Evanston, IL, USA [2] Department of Biomedical Engineering, Northwestern University, Evanston, IL, USA.
authors.forename: K G
authors.initials: KG
authors.lastname: Beaumont
authors.affiliation: Salk Institute for Biological Studies, Laboratory of Genetics, La Jolla, CA, USA.
authors.forename: H J
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: A
authors.initials: A
authors.lastname: Topol
authors.affiliation: 1] 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.
authors.forename: I
authors.initials: I
authors.lastname: Ladran
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: M
authors.initials: M
authors.lastname: Abdelrahim
authors.affiliation: Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: B
authors.initials: B
authors.lastname: Matikainen-Ankney
authors.affiliation: Center for Biosignatures Discovery Automation, Biodesign Institute, Arizona State University Tempe, Arizona, AZ, USA.
authors.forename: S-h
authors.initials: SH
authors.lastname: Chao
authors.affiliation: 1] Departments of Chemistry, Northwestern University, Evanston, IL, USA [2] Department of Biomedical Engineering, Northwestern University, Evanston, IL, USA.
authors.forename: M
authors.initials: M
authors.lastname: Mrksich
authors.affiliation: Department of Neurobiology and Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: P
authors.initials: P
authors.lastname: Rakic
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: G
authors.initials: G
authors.lastname: Fang
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: B
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Yates
authors.affiliation: Salk Institute for Biological Studies, Laboratory of Genetics, La Jolla, CA, USA.
authors.forename: F H
authors.initials: FH
authors.lastname: Gage
mesh_terms: D000328:Adult; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002465:Cell Movement; D002478:Cells, Cultured; D005260:Female; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology; D019006:Neural Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D058953:Neural Stem Cells / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D010641:Phenotype; D039904:Pluripotent Stem Cells / Q000187:drug effects / Q000502:physiology*; D016548:Prosencephalon / Q000473:pathology*; D040901:Proteomics; D017382:Reactive Oxygen Species / Q000378:metabolism; D012559:Schizophrenia / Q000473:pathology*; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; D019006:Neural Cell Adhesion Molecules; D017382:Reactive Oxygen Species