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  • Review Article
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Human induced pluripotent stem cells for modelling neurodevelopmental disorders

Nature Reviews Neurology volume 13, pages 265–278 (2017)Cite this article

Subjects

Key Points

  • Human induced pluripotent stem cells (hiPSCs) are essentially equivalent to embryonic stem cells (ESCs) in that they can differentiate into any adult cell; however, unlike ESCs, hiPSCs can be derived from any somatic cell

  • hiPSCs retain the unique genetic signature of the patient whose somatic cell they were derived from and, therefore, enable us to recapitulate the patient's early development in a dish

  • In the context of neurodevelopmental disorders, hiPSCs enable us to re-enact the altered trajectory of brain development in an individual with disease and simultaneously compare it with normal brain development

  • hiPSC models of neurodevelopmental disorders have not only confirmed the results of pre-existing pathological and genetic studies, they have also elucidated previously unknown facets of these disorders' underlying biology

  • In studying abnormal brain development, hiPSCs can be differentiated into cortical neurons, dopaminergic neurons, astrocytes, etc.; one can even derive 3D organoids in which several brain cell types and tissue layers develop from precursor cells

  • The holy grail of hiPSC models would be to use them as a drug discovery and/or screening platform for neurodevelopmental disorders; promisingly, studies have already made progress towards this goal

Abstract

We currently have a poor understanding of the pathogenesis of neurodevelopmental disorders, owing to the fact that postmortem and imaging studies can only measure the postnatal status quo and offer little insight into the processes that give rise to the observed outcomes. Human induced pluripotent stem cells (hiPSCs) should, in principle, prove powerful for elucidating the pathways that give rise to neurodevelopmental disorders. hiPSCs are embryonic-stem-cell-like cells that can be derived from somatic cells. They retain the unique genetic signature of the individual from whom they were derived, and thus enable researchers to recapitulate that individual's idiosyncratic neural development in a dish. In the case of individuals with disease, we can re-enact the disease-altered trajectory of brain development and examine how and why phenotypic and molecular abnormalities arise in these diseased brains. Here, we review hiPSC biology and possible experimental designs when using hiPSCs to model disease. We then discuss existing hiPSC models of neurodevelopmental disorders. Our hope is that, as some studies have already shown, hiPSCs will illuminate the pathophysiology of developmental disorders of the CNS and lead to therapeutic options for the millions that are affected by these conditions.

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Figure 1: Experimental workflow for hiPSC models of neurodevelopmental disorders.

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Authors and Affiliations

  1. Child Study Center, Yale University School of Medicine, 230 South Frontage Road, New Haven, 06520, Connecticut, USA

    Karthikeyan Ardhanareeswaran, Jessica Mariani, Gianfilippo Coppola & Flora M. Vaccarino

  2. Department of Health Sciences Research, Center for Individualized Medicine, 200 First Street SW, Rochester, 55905, Minnesota, USA

    Alexej Abyzov

  3. Department of Neuroscience, Yale Kavli Institute for Neuroscience, Yale University School of Medicine, 200 South Frontage Road, New Haven, 06510, Connecticut, USA

    Flora M. Vaccarino

Authors
  1. Karthikeyan Ardhanareeswaran
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  2. Jessica Mariani
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  3. Gianfilippo Coppola
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  4. Alexej Abyzov
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  5. Flora M. Vaccarino
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Contributions

All authors researched data for the article, wrote the article and reviewed and/or edited the manuscript before submission. F.M.V. and K.A. made substantial contributions to discussion of the content.

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Correspondence to Flora M. Vaccarino.

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Supplementary information

Supplementary information S1 (table)

hiPSC models of Rett syndrome (PDF 227 kb)

Supplementary information S2 (table)

hiPSC models of fragile X syndrome (PDF 204 kb)

Supplementary information S3 (table)

hiPSC models of Timothy syndrome (PDF 137 kb)

Supplementary information S4 (table)

hiPSC models of autism spectrum disorder (PDF 177 kb)

Supplementary information S5 (table)

hiPSC models of schizophrenia (PDF 206 kb)

PowerPoint slides

Glossary

Preimplantation genetic diagnosis

Screening test used in embryos produced by in vitro fertilization to detect genetic and/or chromosomal disorders.

Somatic cell

Any cell that is not a germ cell (sperm or oocyte) or a one-cell embryo (zygote).

Dual SMAD inhibition method

Method to achieve efficient neural induction of pluripotent stem cells by the synergistic action of two inhibitors of SMAD signalling: Noggin, an inhibitor of bone morphogenetic protein, and SB compound, an inhibitor of lefty–activin–TGFβ pathways.

Isogenic controls

Controls with identical genetic backgrounds as the experimental sample, except for the gene under investigation.

L1 retrotranspositions

Phenomena in which a segment of DNA (known as a retrotransposon) is transcribed into RNA and subsequently reverse-transcribed back into the original DNA sequence, which can be newly inserted into other parts of the genome.

Non-cell-autonomous disorder

A disorder in which mutant cells cause nonmutant cells to exhibit a mutant phenotype.

Tyrosine hydroxylase

An enzyme that converts the amino acid tyrosine to the dopamine precursor, DOPA.

PSD95-protein

Postsynaptic density protein 95 (involved in signalling).

Macrocephaly

An abnormally large head circumference as a result of increased brain size; one of the most consistently replicated phenotypes in ASD, and associated with more-severe symptoms and poorer outcomes.

Canonical β-catenin–BRN2 cascade

Intracellular signalling pathway triggered by the binding of Wnt (Wingless-related integration site) protein to its receptor, culminating with the translocation of the protein β-catenin into the nucleus to act as a transcriptional co-activator of transcription factors that belong to the TCF/LEF family; the gene BRN2 is thought to be a transcriptional target for β-catenin.

Balanced translocation

Chromosomal abnormality in which two nonhomologous chromosomes exchange material in equal amounts (as opposed to unbalanced translocation where the amount of material exchanged is unequal).

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Ardhanareeswaran, K., Mariani, J., Coppola, G. et al. Human induced pluripotent stem cells for modelling neurodevelopmental disorders. Nat Rev Neurol 13, 265–278 (2017). https://doi.org/10.1038/nrneurol.2017.45

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