Concise Review: Induced Pluripotent Stem Cell Models for Neuropsychiatric Diseases

Abstract

The major neuropsychiatric conditions of schizophrenia, affective disorders, and infantile autism are characterized by chronic symptoms of episodic, stable, or progressive nature that result in significant morbidity. Symptomatic treatments are the mainstay but do not resolve the underlying disease processes, which are themselves poorly understood. The prototype psychotropic drugs are of variable efficacy, with therapeutic mechanisms of action that are still uncertain. Thus, neuropsychiatric disorders are ripe for new technologies and approaches with the potential to revolutionize mechanistic understanding and drive the development of novel targeted treatments. The advent of methods to produce patient-derived stem cell models and three-dimensional organoids with the capacity to differentiate into neurons and the various neuronal cellular lineages mark such an advance. We discuss numerous techniques involved, their applications, and areas that require further optimization. Stem Cells Translational Medicine 2017;6:2062-2070.

Keywords: Cell biology; Induced pluripotent stem cells; Nervous system; Reprogramming.

Figure 1

Patient‐derived somatic cells from a patient with neuropsychiatric disease are reprogrammed into hiPSCs via Yamanaka factors. Patient‐specific hiPSCs are then induced to differentiate into NPCs, neurons, and organoids. These disease‐relevant cells provide a platform for research approaches such as transcriptomic, genomic, and biochemical analyses, as well as analyses of neuronal circuit integration, neuronal ion channel properties, neuronal morphology, and other neuronal phenotypes. Abbreviations: hiPSCs, human induced pluripotent stem cells; NPCs, neural progenitor cells.

Figure 2

Organoids can recapitulate normal and abnormal brain development. (A): A human cortical brain section from gestational week 11.5 displays a SOX2+ VZ and TBR2+ SVZ with Ki67+ proliferative cells present in both areas 26. (B): An organoid section labeled with SOX1 and TBR2 antibodies indicates the presence of progenitor regions with the stereotypical structure found in the embryonic brain. Note that organoids do not perfectly replicate the structure of the developing brain, as indicated by the presence of multiple, smaller proliferative zones in the organoid compared with one large proliferative region in the developing cortex. (A, B) Scale bars = 50 μm. Abbreviations: SVZ, subventricular zone; VZ, ventricular zone.