Translation: Screening for Novel Therapeutics With Disease-Relevant Cell Types Derived from Human Stem Cell Models

Abstract

The advent of somatic cell reprogramming technologies, which enables the generation of patient-specific, induced pluripotent stem cell (iPSC) and other trans-differentiated human neuronal cell models, provides new means of gaining insight into the molecular mechanisms and neural substrates of psychiatric disorders. By allowing a more precise understanding of genotype-phenotype relationship in disease-relevant human cell types, the use of reprogramming technologies in tandem with emerging genome engineering approaches provides a previously ‘missing link’ between basic research and translational efforts. In this review, we summarize advances in applying human pluripotent stem cell and reprogramming technologies to generate specific neural subtypes with a focus on the use of these in vitro systems for the discovery of small molecule-probes and novel therapeutics. Examples are given where human cell models of psychiatric disorders have begun to reveal new mechanistic insight into pathophysiology and simultaneously have provided the foundation for developing disease-relevant, phenotypic assays suitable for both functional genomic and chemical screens. A number of areas for future research are discussed, including the need to develop robust methodology for the reproducible, large-scale production of disease-relevant, neural cell types in formats compatible with high-throughput screening modalities, including high-content imaging, multidimensional, signature-based screening, and in vitro network using multielectrode arrays. Limitations, including the challenges in recapitulating neurocircuits and non-cell autonomous phenotypes are discussed. While these technologies are still in active development, we conclude that as our understanding of how to efficiently generate and probe the plasticity of patient-specific stem models improves, their utility is likely to advance rapidly.

Genetics in child and adolescent psychiatry: methodological advances and conceptual issues

“…For instance, one emerging approach uses neurons generated from induced pluripotent stem cells (ipsCs) of individuals carrying specific genetic risk variants. Using so generated neuronal cells may help study the consequences of genetic variance on cellular development, connectivity and synaptic function (e.g., [53]). Another common method using endophenotypes [50] in psychiatric disorders at present is imaging genetics [89].…”

RA Differentiation Enhances Dopaminergic Features, Changes Redox Parameters, and Increases Dopamine Transporter Dependency in 6-Hydroxydopamine-Induced Neurotoxicity in SH-SY5Y Cells

“…Hence, there are limited reliable neuronal in vitro cell models to study PD pathophysiological mechanisms (Radio and Mundy 2008;Haggarty and Perlis 2014).…”

Advancing drug discovery for neuropsychiatric disorders using patient-specific stem cell models

“…While common neuropsychiatric disorders are highly polygenic in nature 2,3 , there are also numerous highly-penetrant, single-gene disorders with relevant neurologic or psychiatric symptomology. The generation of induced pluripotent stem cell (iPSC) models of monogenic or oligogenic neuropsychiatric disorders increasingly provides a powerful means to dissect the underlying disease biology at the level of cells and molecules and to create scalable systems that can support functional genomic and pharmacological screens 4 . This is particularly true for disorders like amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease where cellular phenotypes and cellular context are more well understand and thus able to help define disease-relevant cellular phenotypes 5 .…”

“…While a number of steps in the production of iPSC cells can be automated to allow population-level modeling 81 , there is still a need to develop robust, scalable, functional assays for phenotypic assays and for quantitative biochemistry that are ultimately disease relevant 4 . Related to this issue, one driving question for human iPSC-derived models and therapeutic screening efforts is whether they can be effectively used to model and understand the mechanisms of selective cellular and circuit vulnerability and dysfunction that occur in many neurological and psychiatric disorders 82 .…”