Comparative characterization of human induced pluripotent stem cells (hiPSC) derived from patients with schizophrenia and autism.

Human induced pluripotent stem cells (hiPSC) provide an attractive tool to study disease mechanisms of neurodevelopmental disorders such as schizophrenia. A pertinent problem is the development of hiPSC-based assays to discriminate schizophrenia (SZ) from autism spectrum disorder (ASD) models. Healthy control individuals as well as patients with SZ and ASD were examined by a panel of diagnostic tests. Subsequently, skin biopsies were taken for the generation, differentiation, and testing of hiPSC-derived neurons from all individuals. SZ and ASD neurons share a reduced capacity for cortical differentiation as shown by quantitative analysis of the synaptic marker PSD95 and neurite outgrowth. By contrast, pattern analysis of calcium signals turned out to discriminate among healthy control, schizophrenia, and autism samples. Schizophrenia neurons displayed decreased peak frequency accompanied by increased peak areas, while autism neurons showed a slight decrease in peak amplitudes. For further analysis of the schizophrenia phenotype, transcriptome analyses revealed a clear discrimination among schizophrenia, autism, and healthy controls based on differentially expressed genes. However, considerable differences were still evident among schizophrenia patients under inspection. For one individual with schizophrenia, expression analysis revealed deregulation of genes associated with the major histocompatibility complex class II (MHC class II) presentation pathway. Interestingly, antipsychotic treatment of healthy control neurons also increased MHC class II expression. In conclusion, transcriptome analysis combined with pattern analysis of calcium signals appeared as a tool to discriminate between SZ and ASD phenotypes in vitro.

Influence of field potential duration on spontaneous beating rate of human induced pluripotent stem cell-derived cardiomyocytes: Implications for data analysis and test system selection.

INTRODUCTION: Field potential duration in human pluripotent stem cell (hiPSC)-derived cardiomyocytes is discussed as parameter for the assessment of drug-induced delayed repolarization. In spontaneously beating hiPSC-derived cardiomyocytes field potential duration varies depending on beating rate but beating rate can also be influenced by field potential duration. This interdependence is not fully understood and therefore mandates careful data analysis and cautious interpretation of the results. METHODS: We analysed data from several types of hiPSC-derived cardiomyocytes and, for comparison, primary embryonic chick cardiomyocytes using reference compounds to study the relationship between spontaneous rate and field potential duration. Based on such data we developed a method based on a regression model of drug-induced changes in the inter-beat interval versus changes in the field potential duration to distinguish primary rate from repolarisation effects. RESULTS: We demonstrate the application of this approach with reference and research compounds. Cells from different sources differed with regard to the direct or indirect effects of reference compounds on spontaneous beating. All cell types showed an adaptation of field potential duration upon rate changes induced by reference compounds, however, the adaptation of the spontaneous rate after compound-induced changes in field potential duration varied considerably between cell types. DISCUSSION: As shown by comparison with data from guinea pig papillary muscle, an ex vivo model with a fixed stimulation rate, this approach is more appropriate than the application of correction algorithms routinely used for in vivo data since such algorithms do not account for a dependence of rate on field potential duration.