Integration-free induced pluripotent stem cells derived from schizophrenia patients with a DISC1 mutation

1] Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA [2] The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Molecular Psychiatry (Impact Factor: 14.5). 02/2011; 16(4):358-60. DOI: 10.1038/mp.2011.13
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    • "Additionally, the results reported to date are inconsistent, with studies showing opposite data (Arinola and Idonije, 2009; Rahman et al., 2009). Induced pluripotent stem cells (iPSCs) represent a novel strategy to study psychiatry disorders (Brennand et al., 2011; Chiang et al., 2011; Pedrosa et al., 2011; Paulsen et al., 2012; Robicsek et al., 2013), as they can be differentiated into all cell types, including neurons. Previously, our group showed that neural progenitor cells (NPCs) derived from schizophrenic iPSCs presented increased both extramitochondrial oxygen consumption and reactive oxygen species (ROS), which correlated with the first events associated with the onset of the disease (Paulsen et al., 2012). "
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    ABSTRACT: Schizophrenia has been considered a devastating clinical syndrome rather than a single disease. Nevertheless, the mechanisms behind the onset of schizophrenia have been only partially elucidated. Several studies propose that levels of trace elements are abnormal in schizophrenia; however, conflicting data generated from different biological sources prevent conclusions being drawn. In this work, we used synchrotron radiation X-ray microfluorescence spectroscopy to compare trace element levels in neural progenitor cells (NPCs) derived from two clones of induced pluripotent stem cell lines of a clozapine-resistant schizophrenic patient and two controls. Our data reveal the presence of elevated levels of potassium and zinc in schizophrenic NPCs. Neural cells treated with valproate, an adjunctive medication for schizophrenia, brought potassium and zinc content back to control levels. These results expand the understanding of atomic element imbalance related to schizophrenia and may provide novel insights for the screening of drugs to treat mental disorders.
    Schizophrenia Research 04/2014; 154(1-3). DOI:10.1016/j.schres.2014.02.007 · 3.92 Impact Factor
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    • "Rett ' s syndrome MECP2 , CDKL5 Neurons and neural progenitor cells IGF1 , gentamicin ( Marchetto et al . 2010 ; Muotri et al . 2010 ; Ananiev et al . 2011 ; Cheung et al . 2011 ; Ricciardi et al . 2012 ) Schizophrenia DISC1 , sporadic Neurons Loxapine , valproic acid ( Brennand et al . 2011 ; Chiang et al . 2011 ; Pedrosa et al . 2011 ; Paulsen Bda et al . 2012 ) Spinal muscular atrophy SMN1 Motor neruons Valproic acid , tobramycin ( Ebert et al . 2009 ; Chang et al . 2011 ) Spinal and bulbar muscular atrophy CAG repeat in the androgen receptor gene Motor neurons 17 - allylaminogeldanamycin ( Nihei et al . 2013 ) the LRRK2 , PINK1 , SNCA , PARK"
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    ABSTRACT: Human induced pluripotent stem (iPS) cells obtained by reprogramming technology are a source of great hope, not only in terms of applications in regenerative medicine, such as cell transplantation therapy, but also for modeling human diseases and new drug development. In particular, the production of iPS cells from the somatic cells of patients with intractable diseases and their subsequent differentiation into cells at affected sites (e.g., neurons, cardiomyocytes, hepatocytes, and myocytes) has permitted the in vitro construction of disease models that contain patient-specific genetic information. For example, disease-specific iPS cells have been established from patients with neuropsychiatric disorders, including schizophrenia and autism, as well as from those with neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease. A multi-omics analysis of neural cells originating from patient-derived iPS cells may thus enable investigators to elucidate the pathogenic mechanisms of neurological diseases that have heretofore been unknown. In addition, large-scale screening of chemical libraries with disease-specific iPS cells is currently underway and is expected to lead to new drug discovery. Accordingly, this review outlines the progress made via the use of patient-derived iPS cells toward the modeling of neurological disorders, the testing of existing drugs, and the discovery of new drugs. This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 11/2013; 129(3). DOI:10.1111/jnc.12625 · 4.28 Impact Factor
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    • "As a result, the material for many initial studies was obtained from cell banks with only basic diagnostic and demographic information. More recent studies are making efforts to obtain material from patients subtyped genetically and diagnostically, with more comprehensive clinical data as well as ability for future follow-up studies.33 "
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    ABSTRACT: Human-induced pluripotent stem cells (hiPSCs) derived from somatic cells of patients have opened possibilities for in vitro modeling of the physiology of neural (and other) cells in psychiatric disease states. Issues in early stages of technology development include (1) establishing a library of cells from adequately phenotyped patients, (2) streamlining laborious, costly hiPSC derivation and characterization, (3) assessing whether mutations or other alterations introduced by reprogramming confound interpretation, (4) developing efficient differentiation strategies to relevant cell types, (5) identifying discernible cellular phenotypes meaningful for cyclic, stress induced or relapsing-remitting diseases, (6) converting phenotypes to screening assays suitable for genome-wide mechanistic studies or large collection compound testing and (7) controlling for variability in relation to disease specificity amidst low sample numbers. Coordination of material for reprogramming from patients well-characterized clinically, genetically and with neuroimaging are beginning, and initial studies have begun to identify cellular phenotypes. Finally, several psychiatric drugs have been found to alter reprogramming efficiency in vitro, suggesting further complexity in applying hiPSCs to psychiatric diseases or that some drugs influence neural differentiation moreso than generally recognized. Despite these challenges, studies utilizing hiPSCs may eventually serve to fill essential niches in the translational pipeline for the discovery of new therapeutics.
    11/2013; 45(11):e59. DOI:10.1038/emm.2013.124
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