Modeling complex neuropsychiatric disorders with human induced pluripotent stem cells

Abstract

Identifying the molecular and cellular basis of complex neuropsychiatric disorders (cNPDs) has been limited by the inaccessibility of central neurons, variability within broad diagnostic classifications, and the interplay of genetic and environmental factors. Recent work utilizing neuronally differentiated human induced pluripotent stem cells (hiPSCs) from Mendelian and polygenic cNPDs is beginning to illuminate neuritic, synaptic or cell body variations accompanied by specific gene or protein expression alterations largely mimicking known pathology. In some cases, phenotypes have only emerged after application of cellular stress or long duration of differentiation. Pathological and cellular expression features are fully or partially responsive to pharmacological treatment highlighting the potential utility of differentiated hiPSCs for discovery of personalized therapeutics and for identifying pathogenetically relevant targets in subgroups of patients within a broad syndromic classification. Because of the inherent variability in developing and differentiating hiPSC lines and the multiple comparisons implicit in 'omics' technologies, rigorous algorithms for assuring statistical significance and independent confirmation of results, will be required for robust modeling of cNPDs.

Figure 1. Modeling complex disease and drug discovery with hiPSCs

A. Hypothetical pedigree analysis showing co-segregation of clinical features and measurable hiPSC phenotypes in a family cluster B. Confirmation of original hiPSC phenotype in an independent sample of hiPSC lines from multiple affected and unaffected individuals to validate specificity of hiPSC findings characteristic of the original family C. Three high-throughput screening approaches to utilizing hiPSC cultures: chemical (top) or genetic suppression (middle) to renormalize phenotypic findings observed in affected cases, and genetic screens (bottom) to find candidates that reproduce in normal hiPSC cells the phenotypes of affected individuals. Validation of genetic or chemical intervention in independent sets of patients is required to confirm findings and to understand how broadly in the population the personalized therapeutic approach can be applied.