Development of patient-specific neurons in schizophrenia using induced pluripotent stem cells

J Neurogenet. 2011 Oct;25(3):88-103. doi: 10.3109/01677063.2011.597908. Epub 2011 Jul 29.

Abstract

Induced pluripotent stem cell (iPSC) technology has the potential to transform regenerative medicine. It also offers a powerful tool for establishing in vitro models of disease, in particular, for neuropsychiatric disorders where live human neurons are essentially impossible to procure. Using iPSCs derived from three schizophrenia (SZ) patients, one of whom has 22q11.2del (velocardiofacial syndrome; VCFS), the authors developed a culture system to study SZ on a molecular and cellular level. SZ iPSCs were differentiated into functional, primarily glutamatergic neurons that were able to fire action potentials after ∼8 weeks in culture. Early differentiating neurons expressed a number of transcription factors/chromatin remodeling proteins and synaptic proteins relevant to SZ pathogenesis, including ZNF804A, RELN, CNTNAP2, CTNNA2, SMARCA2, and NRXN1. Although a small number of lines were developed in this preliminary study, the SZ line containing 22q11.2del showed a significant delay in the reduction of endogenous OCT4 and NANOG expression that normally occurs during differentiation. Constitutive expression of OCT4 has been observed in Dgcr8-deficient mouse embryonic stem cells (mESCs); DGCR8 maps to the 22q11.2-deleted region. These findings demonstrate that the method of inducing neural differentiation employed is useful for disease modeling in SZ and that the transition of iPSCs with 22q11.2 deletions towards a differentiated state may be marked by subtle changes in expression of pluripotency-associated genes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Action Potentials / genetics
  • Adult
  • Cell Differentiation / drug effects
  • Cell Differentiation / physiology
  • Cells, Cultured
  • Chromosome Aberrations
  • Chromosome Deletion
  • Chromosomes, Human, 21-22 and Y
  • Computational Biology
  • Embryonic Stem Cells / cytology
  • Embryonic Stem Cells / drug effects
  • Female
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology*
  • Humans
  • Induced Pluripotent Stem Cells / drug effects
  • Induced Pluripotent Stem Cells / physiology*
  • Male
  • Microarray Analysis
  • Middle Aged
  • Nerve Growth Factors / pharmacology
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neurons / physiology*
  • Patch-Clamp Techniques
  • RNA, Messenger / metabolism
  • Schizophrenia / pathology*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Wnt3A Protein / pharmacology
  • Young Adult

Substances

  • Nerve Growth Factors
  • Nerve Tissue Proteins
  • RNA, Messenger
  • Transcription Factors
  • Wnt3A Protein