Phenotypic differences in hiPSC NPCs derived from patients with schizophrenia

K. Brennand, J. N. Savas, Y. Kim, N. Tran, A. Simone, K. Hashimoto-Torii, K. G. Beaumont, H. J. Kim, A. Topol, I. Ladran, M. Abdelrahim, B. Matikainen-Ankney, Shih-Hui Chao, M. Mrksich, P. Rakic, G. Fang, B. Zhang, J. R. Yates, F. H. Gage

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)361-368
Number of pages8
JournalMolecular Psychiatry
Volume20
Issue number3
DOIs
StatePublished - Jan 1 2015

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Induced Pluripotent Stem Cells
Schizophrenia
Stem Cells
Gene Expression
Neurons
Oxidative Stress
Isotope Labeling
Phenotype
Atlases
Brain
Proteomics
Mass Spectrometry
Fetus
Cell Culture Techniques
Amino Acids

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

Brennand, K., Savas, J. N., Kim, Y., Tran, N., Simone, A., Hashimoto-Torii, K., ... Gage, F. H. (2015). Phenotypic differences in hiPSC NPCs derived from patients with schizophrenia. Molecular Psychiatry, 20(3), 361-368. https://doi.org/10.1038/mp.2014.22

Phenotypic differences in hiPSC NPCs derived from patients with schizophrenia. / Brennand, K.; Savas, J. N.; Kim, Y.; Tran, N.; Simone, A.; Hashimoto-Torii, K.; Beaumont, K. G.; Kim, H. J.; Topol, A.; Ladran, I.; Abdelrahim, M.; Matikainen-Ankney, B.; Chao, Shih-Hui; Mrksich, M.; Rakic, P.; Fang, G.; Zhang, B.; Yates, J. R.; Gage, F. H.

In: Molecular Psychiatry, Vol. 20, No. 3, 01.01.2015, p. 361-368.

Research output: Contribution to journalArticle

Brennand, K, Savas, JN, Kim, Y, Tran, N, Simone, A, Hashimoto-Torii, K, Beaumont, KG, Kim, HJ, Topol, A, Ladran, I, Abdelrahim, M, Matikainen-Ankney, B, Chao, S-H, Mrksich, M, Rakic, P, Fang, G, Zhang, B, Yates, JR & Gage, FH 2015, 'Phenotypic differences in hiPSC NPCs derived from patients with schizophrenia', Molecular Psychiatry, vol. 20, no. 3, pp. 361-368. https://doi.org/10.1038/mp.2014.22
Brennand K, Savas JN, Kim Y, Tran N, Simone A, Hashimoto-Torii K et al. Phenotypic differences in hiPSC NPCs derived from patients with schizophrenia. Molecular Psychiatry. 2015 Jan 1;20(3):361-368. https://doi.org/10.1038/mp.2014.22
Brennand, K. ; Savas, J. N. ; Kim, Y. ; Tran, N. ; Simone, A. ; Hashimoto-Torii, K. ; Beaumont, K. G. ; Kim, H. J. ; Topol, A. ; Ladran, I. ; Abdelrahim, M. ; Matikainen-Ankney, B. ; Chao, Shih-Hui ; Mrksich, M. ; Rakic, P. ; Fang, G. ; Zhang, B. ; Yates, J. R. ; Gage, F. H. / Phenotypic differences in hiPSC NPCs derived from patients with schizophrenia. In: Molecular Psychiatry. 2015 ; Vol. 20, No. 3. pp. 361-368.
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