title: Development of patient-specific neurons in schizophrenia using induced pluripotent stem cells.
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.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, New York 10416, USA.
authors.forename: Erika
authors.initials: E
authors.lastname: Pedrosa
authors.forename: Vladislav
authors.initials: V
authors.lastname: Sandler
authors.forename: Abhishek
authors.initials: A
authors.lastname: Shah
authors.forename: Reed
authors.initials: R
authors.lastname: Carroll
authors.forename: Chanjung
authors.initials: C
authors.lastname: Chang
authors.forename: Shira
authors.initials: S
authors.lastname: Rockowitz
authors.forename: Xingyi
authors.initials: X
authors.lastname: Guo
authors.forename: Deyou
authors.initials: D
authors.lastname: Zheng
authors.forename: Herbert M
authors.initials: HM
authors.lastname: Lachman
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000328:Adult; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002869:Chromosome Aberrations; D002872:Chromosome Deletion; D002904:Chromosomes, Human, 21-22 and Y; D019295:Computational Biology; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects / Q000502:physiology*; D008297:Male; D046228:Microarray Analysis; D008875:Middle Aged; D009414:Nerve Growth Factors / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000502:physiology*; D018408:Patch-Clamp Techniques; D012333:RNA, Messenger / Q000378:metabolism; D000091042:Reelin Protein; D012559:Schizophrenia / Q000473:pathology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D060509:Wnt3A Protein / Q000494:pharmacology; D055815:Young Adult
chemical_list: D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D000091042:Reelin Protein; D014157:Transcription Factors; D060509:Wnt3A Protein; C000717127:RELN protein, human; C000717128:Reln protein, mouse