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Opportunities and limitations for studying neuropsychiatric disorders using patient-derived induced pluripotent stem cells

Abstract

Neuropsychiatric disorders affect a large proportion of the global population and there is an urgent need to understand the pathogenesis and to develop novel and improved treatments of these devastating disorders. However, the diverse symptomatology combined with complex polygenic etiology, and the limited access to disorder-relevant cell types in human brains represent a major obstacle for mechanistic disease research. Conventional animal models, such as rodents, are limited by inherent species differences in brain development, architecture, and function. Advances in human induced pluripotent stem cells (hiPSCs) technologies have provided platforms for new discoveries in neuropsychiatric disorders. First, hiPSC-based disease models enable unprecedented investigation of psychiatric disorders at the molecular, cellular, and structural levels. Second, hiPSCs derived from patients with known genetics, symptoms, and drug response profiles offer an opportunity to recapitulate pathogenesis in relevant cell types and provide novel approaches for understanding disease mechanisms and for developing effective treatments. Third, genome-editing technologies have extended the potential of hiPSCs for generating models to elucidate the genetic basis of rare monogenetic and complex polygenic psychiatric disorders and to establish the causality between genotype and phenotype. Here we review opportunities and limitations for studying psychiatric disorders using various hiPSC-derived model systems.

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Fig. 1: Diagram of hiPSC-based models.
Fig. 2: Molecular, cellular, and architectural read-outs for iPSC-based disease modeling.

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Funding

Funding

The research in the authors’ laboratory were supported by grants from the Institutes of Health (R35NS097370, U19AI131130, RF1MH123979, R01MH125528 to GLM, and R35NS116843, U01HG012047, RF1AG079557, and U19MH106434 to H.S.) and from Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (to GLM).

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Hong, Y., Yang, Q., Song, H. et al. Opportunities and limitations for studying neuropsychiatric disorders using patient-derived induced pluripotent stem cells. Mol Psychiatry 28, 1430–1439 (2023). https://doi.org/10.1038/s41380-023-01990-8

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